id: P19544
gene_symbol: WT1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'WT1 (Wilms tumor protein) is a C2H2 zinc-finger transcription factor
  that plays essential roles in urogenital and cardiac development. The protein contains
  an N-terminal proline/glutamine-rich regulatory domain (with separate repression
  and activation domains) and four C-terminal C2H2 zinc fingers (encoded by exons
  7-10) that mediate sequence-specific DNA binding to the motif 5''-GCG(T/G)GGGCG-3''
  with Kd ~1.14 nM. Alternative splicing at intron 9 produces two major isoform classes
  with distinct functions: the -KTS isoform functions as a classical DNA-binding transcription
  factor (both activator and repressor depending on cofactors like BASP1/p53 and cellular
  context), while the +KTS isoform has reduced DNA affinity (due to increased linker
  flexibility between ZnF3-4) and participates in RNA processing, localizing to nuclear
  speckles and interacting with splicing factors (U2AF65, RBM4). The normal +KTS/-KTS
  ratio of ~2:1 is critical; Frasier syndrome results from altered ratio. WT1 functions
  as a tumor suppressor in kidney (loss causes Wilms tumor) but can act as an oncogene
  in AML/leukemias. Key transcriptional targets include nephrin/NPHS1 and podocalyxin
  (activation in podocytes), PAX2 (repression during differentiation), BCL2 and MYC
  (repression for tumor suppression), DNMT3A (activation), and SF1/SRY (activation
  in sex determination). WT1 is essential for: (1) mesenchymal-to-epithelial transition
  during nephrogenesis and podocyte maintenance, (2) gonadal development and sex determination,
  and (3) epicardial epithelial-to-mesenchymal transition for coronary vasculature
  formation via Wnt/beta-catenin and retinoic acid signaling.'
functional_isoforms:
  - id: WT1_MINUS_KTS
    name: "-KTS isoforms"
    type: SPLICE_CLASS
    maps_to:
      - type: UNIPROT_ISOFORM
        ids: [P19544-2, P19544-4]
    description: >
      DNA-binding transcription factors. The -KTS isoforms lack the KTS tripeptide
      (Lys-Thr-Ser) between zinc fingers 3 and 4, resulting in a shorter linker
      that maintains high DNA-binding affinity (Kd ~1 nM) for the consensus motif
      5'-GCG(T/G)GGGCG-3'. These isoforms function as classical transcription factors,
      both activating (SRY, DNMT3A, NPHS1) and repressing (PAX2, BCL2, MYC) target
      genes depending on cofactors and cellular context. The -KTS isoforms are
      essential for kidney development (Wilms tumor suppression) and sex determination.
      PMID:9815658 directly demonstrates SRY promoter activation by -KTS but NOT +KTS.
    isoform_specific_terms:
      - id: GO:0000981
        label: DNA-binding transcription factor activity, RNA polymerase 
          II-specific
      - id: GO:0045944
        label: positive regulation of transcription by RNA polymerase II
      - id: GO:0045892
        label: negative regulation of DNA-templated transcription

  - id: WT1_PLUS_KTS
    name: "+KTS isoforms"
    type: SPLICE_CLASS
    maps_to:
      - type: UNIPROT_ISOFORM
        ids: [P19544-1, P19544-3]
    description: >
      RNA-binding/splicing regulators. The +KTS isoforms have a 3-amino acid insertion
      (Lys-Thr-Ser) between zinc fingers 3 and 4, increasing linker flexibility and
      REDUCING DNA-binding affinity by ~10-fold. These isoforms localize to nuclear
      speckles (not nucleoplasm) and interact with splicing factors (U2AF65, RBM4,
      WTAP). The +KTS isoforms do NOT function as transcription factors - they
      participate in mRNA processing. PMID:9815658 shows +KTS does NOT activate the
      SRY promoter that -KTS strongly activates. Frasier syndrome results from loss
      of +KTS isoforms specifically, demonstrating their distinct developmental role.
      The normal +KTS:-KTS ratio of ~2:1 is critical for proper development.
    isoform_specific_terms:
      - id: GO:0003723
        label: RNA binding
      - id: GO:0016607
        label: nuclear speck
      - id: GO:0000398
        label: mRNA splicing, via spliceosome
existing_annotations:
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: WT1 is well-established as a sequence-specific DNA-binding 
        transcription factor. The -KTS isoform binds with high affinity to the 
        consensus 5'-GCG(T/G)GGGCG-3' motif via its C2H2 zinc fingers 
        [PMID:7862533, PMID:25258363]. Multiple studies demonstrate direct 
        binding to cis-regulatory regions of target genes including PAX2, BCL2, 
        MYC, EGFR, PDGFA, SRY, and DNMT3A promoters.
      action: ACCEPT
      reason: Core molecular function well-supported by extensive biochemical 
        and structural evidence. Crystal structures confirm zinc finger-DNA 
        interactions [PMID:25258363]. This is a fundamental function of the -KTS
        isoform.
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: WT1 functions as both a transcriptional activator and repressor 
        depending on target gene and cellular context. The -KTS isoform is the 
        primary transcription factor form. WT1 activates genes like SRY, DNMT3A,
        and EPO, while repressing PAX2, BCL2, MYC, and EGFR [PMID:9815658, 
        PMID:7720589, PMID:7585606, PMID:23042785].
      action: ACCEPT
      reason: Core molecular function. WT1's role as an RNA Pol II transcription
        factor is foundational to its developmental and tumor suppressor 
        functions. The dual activator/repressor activity is isoform-dependent 
        and context-dependent.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: WT1 is predominantly nuclear, consistent with its role as a 
        transcription factor. Multiple IDA studies confirm nuclear localization 
        [PMID:1662794, PMID:8306891, PMID:7588596]. Both -KTS and +KTS isoforms 
        localize to the nucleus, though with different subnuclear distributions.
      action: ACCEPT
      reason: Core cellular component annotation well-supported by 
        immunofluorescence and biochemical fractionation studies. Nuclear 
        localization is essential for WT1's transcriptional regulatory function.
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: WT1 regulates transcription of numerous target genes via RNA Pol 
        II machinery. It can both activate and repress transcription depending 
        on target and context. Documented targets include PAX2 (repression), 
        BCL2/MYC (repression), DNMT3A (activation), EPO (activation), SRY 
        (activation), and many others [PMID:23042785, PMID:7720589, 
        PMID:7585606, PMID:9815658].
      action: ACCEPT
      reason: Core biological process. Transcriptional regulation is the primary
        function of WT1, underlying its roles in development and tumor 
        suppression.
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: WT1 functions as a tumor suppressor and inhibits cell 
        proliferation. This is mediated through transcriptional repression of 
        growth-promoting genes like BCL2, MYC, and growth factor receptors, as 
        well as through interaction with Hsp70 [PMID:9553041, PMID:7585606].
      action: ACCEPT
      reason: Well-supported tumor suppressor function. WT1 loss leads to 
        uncontrolled proliferation in Wilms tumor. The antiproliferative effect 
        is demonstrated through inducible expression studies [PMID:9553041].
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: WT1 has complex effects on apoptosis. While it represses BCL2 
        which would promote apoptosis [PMID:7585606], developmental studies show
        that WT1 is required for cell survival during nephrogenesis - Wt1 null 
        embryos show apoptosis in the urogenital ridge [PMID:10101119].
      action: KEEP_AS_NON_CORE
      reason: WT1's role in apoptosis regulation is context-dependent and likely
        secondary to its primary transcriptional regulatory functions. The 
        anti-apoptotic effect observed in development may reflect regulation of 
        survival factors rather than direct apoptosis pathway involvement.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: WT1 functions as a transcriptional repressor for multiple target 
        genes including PAX2, BCL2, MYC, EGFR, and AR [PMID:7720589, 
        PMID:7585606, PMID:7588596, PMID:9815658]. This is a well-documented 
        core function, particularly for the -KTS isoform.
      action: ACCEPT
      reason: Although this is an IEA annotation, transcriptional repression is 
        extensively documented by experimental evidence. This represents a core 
        molecular function.
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: WT1 contains four C2H2 zinc fingers that mediate DNA binding. 
        This is a core molecular function, though the more specific term 
        GO:0043565 (sequence-specific DNA binding) is preferable.
      action: ACCEPT
      reason: Valid annotation. While more specific terms exist (GO:0043565, 
        GO:0000978), this general DNA binding annotation is correct and 
        supported by extensive evidence.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: The +KTS isoform of WT1 has documented RNA-binding activity. The 
        zinc finger domain provides overlapping surfaces for DNA and RNA binding
        [bardeesy1998]. The +KTS isoform associates with splicing factors and 
        participates in RNA processing [PMID:16934801].
      action: ACCEPT
      reason: Valid annotation for the +KTS isoform specifically. RNA binding is
        part of WT1's post-transcriptional regulatory functions. Note this is 
        isoform-specific.
      additional_reference_ids:
        - PMID:16934801
      supported_by:
        - reference_id: PMID:16934801
          supporting_text: Epub 2006 Jul 25. WT1 interacts with the splicing 
            protein RBM4 and regulates its ability to modulate alternative 
            splicing in vivo.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Nuclear localization is well-established for WT1, consistent with
        its role as a transcription factor.
      action: ACCEPT
      reason: Duplicate of IBA annotation above. Nuclear localization is 
        well-supported.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: WT1 is present in the nucleoplasm. The -KTS isoform has a diffuse
        nuclear distribution [PMID:15520190], while +KTS localizes more to 
        nuclear speckles.
      action: ACCEPT
      reason: Supported by localization studies. The -KTS isoform particularly 
        shows nucleoplasmic distribution.
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: UniProt indicates nucleolar localization. WT1 has been reported 
        in various nuclear subcompartments.
      action: UNDECIDED
      reason: Nucleolar localization is not prominently featured in the primary 
        literature. The primary nuclear localizations are nucleoplasm (-KTS) and
        nuclear speckles (+KTS). This annotation may represent a minor or 
        transient localization.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: WT1 can shuttle between nucleus and cytoplasm. Cytoplasmic WT1 
        has been associated with polysome-bound mRNPs, supporting 
        post-transcriptional roles.
      action: KEEP_AS_NON_CORE
      reason: While WT1 can be cytoplasmic, the primary localization and 
        function is nuclear. Cytoplasmic localization may relate to RNA 
        processing or shuttling.
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: WT1 is a transcription factor that regulates expression of 
        numerous target genes. This is a core biological process annotation.
      action: ACCEPT
      reason: Core function. Equivalent to the more specific GO:0006357 
        (regulation of transcription by RNA Pol II).
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: WT1 contains four C2H2 zinc finger domains that coordinate zinc 
        ions for structural integrity and DNA binding. Zinc binding is 
        experimentally demonstrated [PMID:15518539, PMID:25258363].
      action: ACCEPT
      reason: Core molecular function. The zinc fingers are essential for DNA 
        binding activity. Structural studies confirm zinc coordination 
        [PMID:15518539].
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: The +KTS isoform of WT1 localizes to nuclear speckles, which are 
        sites of pre-mRNA splicing factor storage and modification 
        [PMID:9553041, PMID:15520190, PMID:16934801].
      action: ACCEPT
      reason: Well-documented localization for the +KTS isoform, consistent with
        its role in RNA processing. Colocalization with RBM4 in speckles is 
        demonstrated.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: WT1 binds zinc ions via its C2H2 zinc finger domains. This is 
        correct but redundant with the more specific GO:0008270 (zinc ion 
        binding).
      action: ACCEPT
      reason: Valid but less informative than GO:0008270. Both terms are 
        appropriate.
  - term:
      id: GO:0072078
      label: nephron tubule morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: WT1 is essential for nephrogenesis. Wt1 knockout mice show 
        complete failure of kidney development [PMID:10101119]. WT1 regulates 
        genes required for nephron formation and glomerular development.
      action: ACCEPT
      reason: Well-supported developmental role. WT1 is required throughout 
        nephrogenesis, including tubule formation. This is a core biological 
        process for WT1.
  - term:
      id: GO:0072359
      label: circulatory system development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: WT1 is expressed in the epicardium and is required for heart 
        development. Wt1 null mice die at E13.5 due to heart failure with 
        pericardial bleeding [PMID:10101119].
      action: KEEP_AS_NON_CORE
      reason: Valid annotation but represents a secondary developmental role. 
        The primary functions of WT1 are in kidney and gonad development. Heart 
        involvement is through epicardial/mesothelial functions.
  - term:
      id: GO:1990837
      label: sequence-specific double-stranded DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: WT1 binds sequence-specifically to double-stranded DNA containing
        the motif 5'-GCG(T/G)GGGCG-3'. Crystal structures confirm this binding 
        mode [PMID:25258363].
      action: ACCEPT
      reason: Core molecular function. Equivalent to GO:0043565 which has 
        experimental support.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19447967
    review:
      summary: High-throughput interaction study (Shifted Transversal Design 
        smart-pooling). Interaction with DVL3 (Dishevelled 3) reported.
      action: KEEP_AS_NON_CORE
      reason: '"Protein binding" is an uninformative term. The specific interaction
        partner (DVL3) is identified but functional significance for WT1 is unclear.
        Retain as evidence of protein interaction capacity but not informative about
        core function.'
      supported_by:
        - reference_id: PMID:19447967
          supporting_text: Shifted Transversal Design smart-pooling for high 
            coverage interactome mapping.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21900206
    review:
      summary: High-throughput directed protein interaction network study. 
        Interaction with DVL3.
      action: KEEP_AS_NON_CORE
      reason: Uninformative term from high-throughput study. The specific 
        interaction (DVL3) lacks clear functional context for WT1 biology.
      supported_by:
        - reference_id: PMID:21900206
          supporting_text: A directed protein interaction network for 
            investigating intracellular signal transduction.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: Large-scale human interactome mapping study. Interactions with 
        KRTAP10-8 and KRT40.
      action: KEEP_AS_NON_CORE
      reason: High-throughput study. Keratin-associated proteins are not 
        obviously relevant to known WT1 biology. May represent non-specific 
        interactions.
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome 
            network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25601757
    review:
      summary: WT1 recruits TET2 to regulate target gene expression and suppress
        leukemia cell proliferation. This represents a functionally important 
        interaction.
      action: MODIFY
      reason: This is a functionally significant interaction with TET2 
        (methylcytosine dioxygenase) involved in epigenetic regulation. The 
        generic "protein binding" term does not capture the functional 
        significance.
      proposed_replacement_terms:
        - id: GO:0140678
          label: molecular function activator activity
      supported_by:
        - reference_id: PMID:25601757
          supporting_text: 2015 Jan 15. WT1 recruits TET2 to regulate its target
            gene expression and suppress leukemia cell proliferation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27229929
    review:
      summary: Interactome mapping of ALL cancer gene products. WT1-DVL3 
        interaction.
      action: KEEP_AS_NON_CORE
      reason: Uninformative term. Part of cancer gene product interactome study.
        DVL3 interaction functional significance unclear.
      supported_by:
        - reference_id: PMID:27229929
          supporting_text: Systematic interactome mapping of acute lymphoblastic
            leukemia cancer gene products reveals EXT-1 tumor suppressor as a 
            Notch1 and FBWX7 common interactor.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31515488
    review:
      summary: Study of genetic variants disrupting protein interactions. 
        Interaction with KRT40.
      action: KEEP_AS_NON_CORE
      reason: Uninformative term. Keratin interaction not obviously relevant to 
        WT1 function.
      supported_by:
        - reference_id: PMID:31515488
          supporting_text: Extensive disruption of protein interactions by 
            genetic variants across the allele frequency spectrum in human 
            populations.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9553041
    review:
      summary: WT1 interacts with Hsp70 (HSPA1A/HSPA1B). This is a functionally 
        important interaction required for WT1's growth suppression activity 
        [PMID:9553041].
      action: MODIFY
      reason: Functionally significant interaction. Hsp70 binding is required 
        for WT1 antiproliferative function. Should be annotated with a more 
        specific term.
      proposed_replacement_terms:
        - id: GO:0051087
          label: chaperone binding
      supported_by:
        - reference_id: PMID:9553041
          supporting_text: Inhibition of cellular proliferation by the Wilms 
            tumor suppressor WT1 requires association with the inducible 
            chaperone Hsp70.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7720589
    review:
      summary: WT1 interacts with PAX2, its transcriptional target. The study 
        demonstrates WT1 binding to PAX2 regulatory sequences and repression of 
        PAX2 expression.
      action: MODIFY
      reason: This represents DNA binding to PAX2 promoter rather than 
        protein-protein interaction. The IPI annotation may be misattributed.
      proposed_replacement_terms:
        - id: GO:0000976
          label: transcription cis-regulatory region binding
      supported_by:
        - reference_id: PMID:7720589
          supporting_text: Repression of Pax-2 by WT1 during normal kidney 
            development.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16934801
    review:
      summary: WT1 interacts with RBM4, a splicing regulator. The +KTS isoform 
        specifically modulates RBM4's effect on alternative splicing 
        [PMID:16934801].
      action: MODIFY
      reason: Functionally significant interaction related to WT1's RNA 
        processing function. Should use a more specific MF term.
      proposed_replacement_terms:
        - id: GO:0140678
          label: molecular function activator activity
      supported_by:
        - reference_id: PMID:16934801
          supporting_text: Epub 2006 Jul 25. WT1 interacts with the splicing 
            protein RBM4 and regulates its ability to modulate alternative 
            splicing in vivo.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21390327
    review:
      summary: WT1 interacts with PINCH1 (LIMS1). PINCH1 represses podocalyxin 
        expression and interacts with WT1 in podocytes.
      action: KEEP_AS_NON_CORE
      reason: PINCH1 interaction is documented but the term "protein binding" is
        uninformative. The functional significance relates to podocyte gene 
        regulation.
      supported_by:
        - reference_id: PMID:21390327
          supporting_text: PINCH1 is transcriptional regulator in podocytes that
            interacts with WT1 and represses podocalyxin expression.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14701728
    review:
      summary: WT1 interacts with BASP1, a transcriptional cosuppressor. BASP1 
        binding converts WT1 from an activator to a repressor at specific 
        promoters.
      action: MODIFY
      reason: Functionally important interaction that modulates WT1's 
        transcriptional activity. BASP1 is a documented WT1 cofactor.
      proposed_replacement_terms:
        - id: GO:0003714
          label: transcription corepressor activity
      supported_by:
        - reference_id: PMID:14701728
          supporting_text: BASP1 is a transcriptional cosuppressor for the 
            Wilms' tumor suppressor protein WT1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9178767
    review:
      summary: WT1 interacts with PAX2. PAX2 regulates WT1 promoter activity in 
        a reciprocal regulatory relationship.
      action: KEEP_AS_NON_CORE
      reason: Documents interaction between two kidney development transcription
        factors. Generic term is uninformative.
      supported_by:
        - reference_id: PMID:9178767
          supporting_text: Differential regulation of the human Wilms tumour 
            suppressor gene (WT1) promoter by two isoforms of PAX2.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:8119964
    review:
      summary: WT1 can form homodimers and binds to its own promoter for 
        autoregulation. The interaction is via the zinc finger domain (C2H2 zinc
        finger domain binding).
      action: ACCEPT
      reason: Documents WT1 homodimerization. Also annotated with GO:0070742 
        (C2H2 zinc finger domain binding) which is more specific.
      supported_by:
        - reference_id: PMID:8119964
          supporting_text: The Wilms' tumor suppressor gene WT1 is negatively 
            autoregulated.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: HPA immunofluorescence data showing nucleoplasmic localization.
      action: ACCEPT
      reason: Supported by imaging data. Consistent with WT1's nuclear 
        transcription factor function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: HPA immunofluorescence data indicating cytosolic presence.
      action: KEEP_AS_NON_CORE
      reason: WT1 can shuttle to cytoplasm but primary function is nuclear. 
        Cytosolic localization may relate to shuttling or RNA processing 
        functions.
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: IDA
    original_reference_id: PMID:25258363
    review:
      summary: Crystal structure of WT1 zinc finger domain bound to DNA confirms
        zinc coordination in C2H2 zinc fingers [PMID:25258363].
      action: ACCEPT
      reason: Core molecular function confirmed by structural biology.
      supported_by:
        - reference_id: PMID:25258363
          supporting_text: Sep 25. Wilms tumor protein recognizes 
            5-carboxylcytosine within a specific DNA sequence.
  - term:
      id: GO:0010385
      label: double-stranded methylated DNA binding
    evidence_type: IDA
    original_reference_id: PMID:25258363
    review:
      summary: WT1 can bind to methylated DNA. The study shows WT1 has slightly 
        higher affinity for 5mC-containing sequences compared to unmethylated, 
        but much lower affinity for oxidized forms (5hmC, 5fC, 5caC) 
        [PMID:25258363].
      action: ACCEPT
      reason: Directly demonstrated by biochemical and structural studies. This 
        is a specialized aspect of WT1's DNA binding activity.
      supported_by:
        - reference_id: PMID:25258363
          supporting_text: Sep 25. Wilms tumor protein recognizes 
            5-carboxylcytosine within a specific DNA sequence.
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IDA
    original_reference_id: PMID:25258363
    review:
      summary: WT1 binds to the consensus sequence 5'-GCG(T/G)GGGCG-3' with high
        affinity and specificity [PMID:25258363, PMID:7862533].
      action: ACCEPT
      reason: Core molecular function demonstrated by multiple methods including
        gel shift, footprinting, and X-ray crystallography.
      supported_by:
        - reference_id: PMID:25258363
          supporting_text: Sep 25. Wilms tumor protein recognizes 
            5-carboxylcytosine within a specific DNA sequence.
  - term:
      id: GO:0044729
      label: hemi-methylated DNA-binding
    evidence_type: IDA
    original_reference_id: PMID:25258363
    review:
      summary: Study demonstrates WT1 can bind hemi-methylated DNA substrates 
        [PMID:25258363].
      action: ACCEPT
      reason: Directly demonstrated in the structural/biochemical study.
      supported_by:
        - reference_id: PMID:25258363
          supporting_text: Sep 25. Wilms tumor protein recognizes 
            5-carboxylcytosine within a specific DNA sequence.
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IDA
    original_reference_id: PMID:9553041
    review:
      summary: WT1 localizes to nuclear speckles, particularly the +KTS isoform 
        which colocalizes with splicing factors [PMID:9553041, PMID:16934801].
      action: ACCEPT
      reason: Isoform-specific localization related to RNA processing function.
      supported_by:
        - reference_id: PMID:9553041
          supporting_text: Inhibition of cellular proliferation by the Wilms 
            tumor suppressor WT1 requires association with the inducible 
            chaperone Hsp70.
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IDA
    original_reference_id: PMID:23042785
    review:
      summary: ChIP assays demonstrate WT1 recruitment to the DNMT3A promoter 
        region [PMID:23042785].
      action: ACCEPT
      reason: Core molecular function demonstrated by chromatin 
        immunoprecipitation.
      supported_by:
        - reference_id: PMID:23042785
          supporting_text: 'Chromatin immunoprecipitation assays demonstrate WT1 recruitment
            to the DNMT3A promoter region'
  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:23042785
    review:
      summary: WT1 directly transactivates DNMT3A expression. Reporter assays 
        confirm transcriptional activation [PMID:23042785].
      action: ACCEPT
      reason: Core molecular function. WT1 activates transcription of multiple 
        target genes including DNMT3A, EPO, and SRY.
      supported_by:
        - reference_id: PMID:23042785
          supporting_text: 'reporter assays confirm that WT1 directly transactivates
            DNMT3A expression'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16934801
    review:
      summary: Immunofluorescence shows nuclear localization of WT1 
        [PMID:16934801].
      action: ACCEPT
      reason: Duplicate of multiple other annotations. Nuclear localization is 
        core.
      supported_by:
        - reference_id: PMID:16934801
          supporting_text: Epub 2006 Jul 25. WT1 interacts with the splicing 
            protein RBM4 and regulates its ability to modulate alternative 
            splicing in vivo.
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IDA
    original_reference_id: PMID:16934801
    review:
      summary: WT1 colocalizes with RBM4 in nuclear speckles [PMID:16934801].
      action: ACCEPT
      reason: Consistent with +KTS isoform's role in RNA processing.
      supported_by:
        - reference_id: PMID:16934801
          supporting_text: Epub 2006 Jul 25. WT1 interacts with the splicing 
            protein RBM4 and regulates its ability to modulate alternative 
            splicing in vivo.
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IDA
    original_reference_id: PMID:7720589
    review:
      summary: DNase I footprinting demonstrates WT1 binding to specific sites 
        in the PAX2 promoter [PMID:7720589].
      action: ACCEPT
      reason: Core molecular function demonstrated by direct biochemical assay.
      supported_by:
        - reference_id: PMID:7720589
          supporting_text: Repression of Pax-2 by WT1 during normal kidney 
            development.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:7720589
    review:
      summary: WT1 represses PAX2 transcription. Co-transfection assays 
        demonstrate WT1-dependent transcriptional repression [PMID:7720589].
      action: ACCEPT
      reason: Core function. WT1 represses multiple target genes. PAX2 
        repression is important for kidney development.
      supported_by:
        - reference_id: PMID:7720589
          supporting_text: Repression of Pax-2 by WT1 during normal kidney 
            development.
  - term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    evidence_type: IDA
    original_reference_id: PMID:9815658
    review:
      summary: EMSA shows WT1 binding to promoter elements of SRY, MIS, and 
        androgen receptor genes [PMID:9815658].
      action: ACCEPT
      reason: Core molecular function demonstrated for multiple target gene 
        promoters.
      supported_by:
        - reference_id: PMID:9815658
          supporting_text: "The Wilms' tumor gene WT1 can regulate genes involved
            in sex determination and differentiation: SRY, Müllerian-inhibiting substance,
            and the androgen receptor."
  - term:
      id: GO:0007530
      label: sex determination
    evidence_type: IDA
    original_reference_id: PMID:9815658
    review:
      summary: WT1 regulates transcription of sex determination genes SRY, MIS, 
        and androgen receptor [PMID:9815658]. Genital abnormalities in DDS 
        patients and Wt1 knockout mice support this role.
      action: ACCEPT
      reason: Core biological process. WT1 is essential for gonadal development 
        and sex determination, regulating key genes in the pathway.
      supported_by:
        - reference_id: PMID:9815658
          supporting_text: "The Wilms' tumor gene WT1 can regulate genes involved
            in sex determination and differentiation: SRY, Müllerian-inhibiting substance,
            and the androgen receptor."
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IDA
    original_reference_id: PMID:1662794
    review:
      summary: WT1 binds to the EGR consensus sequence in gel-retardation assays
        [PMID:1662794].
      action: ACCEPT
      reason: One of the earliest demonstrations of WT1's sequence-specific DNA 
        binding.
      supported_by:
        - reference_id: PMID:1662794
          supporting_text: Characterization of the zinc finger protein encoded 
            by the WT1 Wilms' tumor locus.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:8132626
    review:
      summary: WT1 activates transcription in certain contexts.
      action: ACCEPT
      reason: Core function. WT1 can act as both activator and repressor.
      supported_by:
        - reference_id: PMID:8132626
          supporting_text: Transcriptional regulation of the human Wilms' tumor 
            gene (WT1).
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:21390327
    review:
      summary: WT1 regulates podocalyxin expression in podocytes.
      action: ACCEPT
      reason: Supports WT1's role in podocyte gene regulation.
      supported_by:
        - reference_id: PMID:21390327
          supporting_text: PINCH1 is transcriptional regulator in podocytes that
            interacts with WT1 and represses podocalyxin expression.
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IDA
    original_reference_id: PMID:9553041
    review:
      summary: Inducible WT1 expression inhibits cellular proliferation. This 
        requires association with Hsp70 [PMID:9553041].
      action: ACCEPT
      reason: Core tumor suppressor function demonstrated by inducible 
        expression studies.
      supported_by:
        - reference_id: PMID:9553041
          supporting_text: Inhibition of cellular proliferation by the Wilms 
            tumor suppressor WT1 requires association with the inducible 
            chaperone Hsp70.
  - term:
      id: GO:0030308
      label: negative regulation of cell growth
    evidence_type: IDA
    original_reference_id: PMID:9553041
    review:
      summary: WT1 inhibits cell growth [PMID:9553041].
      action: ACCEPT
      reason: Related to tumor suppressor function. Equivalent to GO:0008285.
      supported_by:
        - reference_id: PMID:9553041
          supporting_text: Inhibition of cellular proliferation by the Wilms 
            tumor suppressor WT1 requires association with the inducible 
            chaperone Hsp70.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:9178767
    review:
      summary: PMID:9178767 investigates PAX2 regulation of the WT1 promoter, 
        not WT1's transcriptional activity. The study shows "PAX2 transactivated
        the WT1 promoter up to 35-fold" - this is PAX2's function, not WT1's.
      action: REMOVE
      reason: This annotation is incorrectly attributed. The referenced paper 
        demonstrates that PAX2 activates WT1 transcription (PAX2 -> WT1), not 
        that WT1 positively regulates other genes. This should be an annotation 
        on PAX2, not WT1.
      supported_by:
        - reference_id: PMID:9178767
          supporting_text: Differential regulation of the human Wilms tumour 
            suppressor gene (WT1) promoter by two isoforms of PAX2.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:9553041
    review:
      summary: WT1 can activate transcription of certain target genes.
      action: ACCEPT
      reason: WT1 has dual activator/repressor function.
      supported_by:
        - reference_id: PMID:9553041
          supporting_text: Inhibition of cellular proliferation by the Wilms 
            tumor suppressor WT1 requires association with the inducible 
            chaperone Hsp70.
  - term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    evidence_type: IDA
    original_reference_id: PMID:7588596
    review:
      summary: WT1 binds to EGFR promoter elements [PMID:7588596].
      action: ACCEPT
      reason: Core molecular function for regulation of EGFR.
      supported_by:
        - reference_id: PMID:7588596
          supporting_text: WT1 suppresses synthesis of the epidermal growth 
            factor receptor and induces apoptosis.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:9815658
    review:
      summary: WT1 represses transcription of MIS and androgen receptor genes 
        [PMID:9815658].
      action: ACCEPT
      reason: Core repressor function on sex determination genes.
      supported_by:
        - reference_id: PMID:9815658
          supporting_text: "The Wilms' tumor gene WT1 can regulate genes involved
            in sex determination and differentiation: SRY, Müllerian-inhibiting substance,
            and the androgen receptor."
    isoform: P19544-1
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: IDA
    original_reference_id: PMID:15518539
    review:
      summary: NMR structure of WT1 zinc fingers in complex with zinc 
        [PMID:15518539].
      action: ACCEPT
      reason: Structural confirmation of zinc binding.
      supported_by:
        - reference_id: PMID:15518539
          supporting_text: 'Why zinc fingers prefer zinc: ligand-field symmetry and
            the hidden thermodynamics of metal ion selectivity.'
  - term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    evidence_type: IDA
    original_reference_id: PMID:1332065
    review:
      summary: WT1 binds to PDGFA promoter [PMID:1332065].
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:1332065
          supporting_text: Human platelet-derived growth factor A chain is 
            transcriptionally repressed by the Wilms tumor suppressor WT1.
  - term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    evidence_type: IDA
    original_reference_id: PMID:7585606
    review:
      summary: WT1 binds to BCL2 and MYC promoter elements [PMID:7585606].
      action: ACCEPT
      reason: Core molecular function for tumor suppressor activity.
      supported_by:
        - reference_id: PMID:7585606
          supporting_text: Regulation of the proto-oncogenes bcl-2 and c-myc by 
            the Wilms' tumor suppressor gene WT1.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:1332065
    review:
      summary: WT1 represses PDGFA transcription.
      action: ACCEPT
      reason: Core repressor function.
      supported_by:
        - reference_id: PMID:1332065
          supporting_text: Human platelet-derived growth factor A chain is 
            transcriptionally repressed by the Wilms tumor suppressor WT1.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:7585606
    review:
      summary: WT1 represses BCL2 and MYC transcription [PMID:7585606].
      action: ACCEPT
      reason: Core tumor suppressor function.
      supported_by:
        - reference_id: PMID:7585606
          supporting_text: Regulation of the proto-oncogenes bcl-2 and c-myc by 
            the Wilms' tumor suppressor gene WT1.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:7588596
    review:
      summary: Nuclear localization confirmed.
      action: ACCEPT
      reason: Duplicate annotation. Nuclear localization is core.
      supported_by:
        - reference_id: PMID:7588596
          supporting_text: WT1 suppresses synthesis of the epidermal growth 
            factor receptor and induces apoptosis.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:14701728
    review:
      summary: Nuclear localization confirmed.
      action: ACCEPT
      reason: Duplicate annotation.
      supported_by:
        - reference_id: PMID:14701728
          supporting_text: BASP1 is a transcriptional cosuppressor for the 
            Wilms' tumor suppressor protein WT1.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:14701728
    review:
      summary: WT1 with BASP1 represses transcription [PMID:14701728].
      action: ACCEPT
      reason: Core function. BASP1 modulates WT1's repressor activity.
      supported_by:
        - reference_id: PMID:14701728
          supporting_text: BASP1 is a transcriptional cosuppressor for the 
            Wilms' tumor suppressor protein WT1.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:19050011
    review:
      summary: Dynamic WT1-BASP1 interaction regulates transcription during 
        differentiation.
      action: ACCEPT
      reason: Supports repressor function.
      supported_by:
        - reference_id: PMID:19050011
          supporting_text: Dec 2. Dynamic interaction between WT1 and BASP1 in 
            transcriptional regulation during differentiation.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:14701728
    review:
      summary: WT1 without BASP1 can activate transcription.
      action: ACCEPT
      reason: Dual activator/repressor function depends on cofactor context.
      supported_by:
        - reference_id: PMID:14701728
          supporting_text: BASP1 is a transcriptional cosuppressor for the 
            Wilms' tumor suppressor protein WT1.
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IDA
    original_reference_id: PMID:9765217
    review:
      summary: WT1 induces RbAp46 which mediates growth inhibition 
        [PMID:9765217].
      action: ACCEPT
      reason: Tumor suppressor mechanism.
      supported_by:
        - reference_id: PMID:9765217
          supporting_text: Induction of Rb-associated protein (RbAp46) by Wilms'
            tumor suppressor WT1 mediates growth inhibition.
  - term:
      id: GO:0030308
      label: negative regulation of cell growth
    evidence_type: IDA
    original_reference_id: PMID:9765217
    review:
      summary: WT1-induced growth inhibition via RbAp46.
      action: ACCEPT
      reason: Related to tumor suppressor function.
      supported_by:
        - reference_id: PMID:9765217
          supporting_text: Induction of Rb-associated protein (RbAp46) by Wilms'
            tumor suppressor WT1 mediates growth inhibition.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:9765217
    review:
      summary: WT1 activates RbAp46 transcription.
      action: ACCEPT
      reason: WT1 can activate transcription of certain targets.
      supported_by:
        - reference_id: PMID:9765217
          supporting_text: Induction of Rb-associated protein (RbAp46) by Wilms'
            tumor suppressor WT1 mediates growth inhibition.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:1662794
    review:
      summary: Immunofluorescence shows nuclear localization [PMID:1662794].
      action: ACCEPT
      reason: Core localization.
      supported_by:
        - reference_id: PMID:1662794
          supporting_text: Characterization of the zinc finger protein encoded 
            by the WT1 Wilms' tumor locus.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:8306891
    review:
      summary: Nuclear localization in embryonic and adult tissues.
      action: ACCEPT
      reason: Core localization.
      supported_by:
        - reference_id: PMID:8306891
          supporting_text: Nuclear localization of the protein encoded by the 
            Wilms' tumor gene WT1 in embryonic and adult tissues.
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IDA
    original_reference_id: PMID:8119964
    review:
      summary: WT1 binds specifically to its own promoter for autoregulation.
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:8119964
          supporting_text: The Wilms' tumor suppressor gene WT1 is negatively 
            autoregulated.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:12802290
    review:
      summary: WT1 regulates c-MYC expression. c-MYC is upregulated in 
        WT1-mutant tumors.
      action: ACCEPT
      reason: Core tumor suppressor mechanism.
      supported_by:
        - reference_id: PMID:12802290
          supporting_text: "Upregulation of c-MYC in WT1-mutant tumors: assessment
            of WT1 putative transcriptional targets using cDNA microarray expression
            profiling of genetically defined Wilms' tumors."
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:8119964
    review:
      summary: WT1 negatively autoregulates its own expression.
      action: ACCEPT
      reason: Autoregulatory repression.
      supported_by:
        - reference_id: PMID:8119964
          supporting_text: The Wilms' tumor suppressor gene WT1 is negatively 
            autoregulated.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:12802290
    review:
      summary: PMID:12802290 shows "c-MYC...was upregulated in WT1-mutant 
        tumors", meaning WT1 normally represses c-MYC. The paper states WT1 
        "represses or activates the expression of a variety of putative target 
        genes" but the specific finding for c-MYC supports repression.
      action: REMOVE
      reason: This annotation contradicts the evidence in the referenced paper. 
        PMID:12802290 demonstrates that c-MYC is upregulated when WT1 is 
        mutated, indicating WT1 normally represses (not activates) c-MYC 
        transcription. The negative regulation annotation from this paper is 
        correct; this positive regulation annotation is erroneous.
      supported_by:
        - reference_id: PMID:12802290
          supporting_text: "Upregulation of c-MYC in WT1-mutant tumors: assessment
            of WT1 putative transcriptional targets using cDNA microarray expression
            profiling of genetically defined Wilms' tumors."
  - term:
      id: GO:0070742
      label: C2H2 zinc finger domain binding
    evidence_type: IPI
    original_reference_id: PMID:8119964
    review:
      summary: WT1 homodimerizes via zinc finger domains.
      action: ACCEPT
      reason: Specific molecular function for homodimerization.
      supported_by:
        - reference_id: PMID:8119964
          supporting_text: The Wilms' tumor suppressor gene WT1 is negatively 
            autoregulated.
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IDA
    original_reference_id: PMID:15520190
    review:
      summary: +KTS isoform (isoform 1) localizes to nuclear speckles 
        [PMID:15520190].
      action: ACCEPT
      reason: Isoform-specific localization related to RNA processing.
      supported_by:
        - reference_id: PMID:15520190
          supporting_text: SUMO-1 modification of the Wilms' tumor suppressor 
            WT1.
    isoform: P19544-1
  - term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    evidence_type: IDA
    original_reference_id: PMID:16467207
    review:
      summary: WT1 binds to erythropoietin (EPO) gene promoter [PMID:16467207].
      action: ACCEPT
      reason: Core molecular function for EPO regulation.
      supported_by:
        - reference_id: PMID:16467207
          supporting_text: Feb 7. Wilms tumor suppressor, Wt1, is a 
            transcriptional activator of the erythropoietin gene.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:16467207
    review:
      summary: WT1 activates EPO gene transcription [PMID:16467207].
      action: ACCEPT
      reason: Core activator function.
      supported_by:
        - reference_id: PMID:16467207
          supporting_text: Feb 7. Wilms tumor suppressor, Wt1, is a 
            transcriptional activator of the erythropoietin gene.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:7585606
    review:
      summary: WT1 represses BCL2 and MYC via RNA Pol II [PMID:7585606].
      action: ACCEPT
      reason: Core repressor function.
      supported_by:
        - reference_id: PMID:7585606
          supporting_text: Regulation of the proto-oncogenes bcl-2 and c-myc by 
            the Wilms' tumor suppressor gene WT1.
  - term:
      id: GO:0044027
      label: negative regulation of gene expression via chromosomal CpG island 
        methylation
    evidence_type: IMP
    original_reference_id: PMID:23042785
    review:
      summary: WT1 regulates DNMT3A, leading to DNA methylation changes at 
        specific promoters. WT1 overexpression causes hypermethylation and 
        silencing [PMID:23042785].
      action: ACCEPT
      reason: Novel regulatory function linking WT1 to epigenetic regulation via
        DNMT3A. Well-supported by the study.
      supported_by:
        - reference_id: PMID:23042785
          supporting_text: 'human embryonal kidney cells over-expressing WT1 acquire
            DNA methylation changes at specific gene promoters where DNMT3A recruitment
            is increased, with hypermethylation being associated with silencing of
            gene expression'
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:23042785
    review:
      summary: WT1 depletion affects transcription of methylated genes.
      action: ACCEPT
      reason: Supported by knockdown studies in the paper.
      supported_by:
        - reference_id: PMID:23042785
          supporting_text: 'depletion of WT1 in Wilms'' tumour cells can lead to reactivation
            of gene expression from methylated promoters'
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:23042785
    review:
      summary: WT1 positively regulates DNMT3A expression.
      action: ACCEPT
      reason: Direct evidence from the study.
      supported_by:
        - reference_id: PMID:23042785
          supporting_text: 'depletion of WT1 by short-interfering RNAs leads to reduced
            DNMT3A in Wilms'' tumour cells'
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:23042785
    review:
      summary: WT1 activates DNMT3A transcription.
      action: ACCEPT
      reason: Core activator function demonstrated by reporter assays.
      supported_by:
        - reference_id: PMID:23042785
          supporting_text: 'Wilms'' tumour 1 (WT1), a developmental master regulator
            that can also act as a tumour suppressor or oncoprotein, transcriptionally
            regulates the de novo DNA methyltransferase 3A (DNMT3A)'
  - term:
      id: GO:1902895
      label: positive regulation of miRNA transcription
    evidence_type: IMP
    original_reference_id: PMID:23042785
    review:
      summary: WT1 may regulate miRNA transcription through DNMT3A-mediated 
        epigenetic effects.
      action: UNDECIDED
      reason: The PMID:23042785 paper focuses on DNMT3A regulation. The 
        connection to miRNA transcription is not directly documented in the 
        abstract. Need to verify this specific claim.
      supported_by:
        - reference_id: PMID:23042785
          supporting_text: Control of epigenetic states by WT1 via regulation of
            de novo DNA methyltransferase 3A.
  - term:
      id: GO:0032836
      label: glomerular basement membrane development
    evidence_type: IMP
    original_reference_id: PMID:19205749
    review:
      summary: WT1 mutation associated with glomerular defects.
      action: ACCEPT
      reason: WT1 is essential for podocyte function and glomerular development.
        Mutations cause glomerular disease.
      supported_by:
        - reference_id: PMID:19205749
          supporting_text: 2009 Feb 11. Membranoproliferative glomerulonephritis
            associated with a mutation in Wilms' tumour suppressor gene 1.
  - term:
      id: GO:0007507
      label: heart development
    evidence_type: IGI
    original_reference_id: PMID:10101119
    review:
      summary: Wt1 knockout mice show heart defects with pericardial bleeding. 
        YAC rescue experiments demonstrate WT1 requirement for heart development
        [PMID:10101119].
      action: KEEP_AS_NON_CORE
      reason: Valid developmental role but secondary to kidney/gonad functions. 
        Heart involvement is through epicardial development.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: 'Lack of WT1 leads to severe defects in the epicardial
            layer and a concomitant absence of SEMCs, which explains the pericardial
            bleeding and subsequent embryonic death observed in Wt1 null embryos'
  - term:
      id: GO:0030325
      label: adrenal gland development
    evidence_type: IGI
    original_reference_id: PMID:10101119
    review:
      summary: Partially rescued Wt1 mutant embryos show severely affected 
        adrenal gland development [PMID:10101119].
      action: KEEP_AS_NON_CORE
      reason: Valid developmental role but less prominent than kidney/gonad. 
        Related to WT1's role in intermediate mesoderm-derived organs.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: 'the development of adrenal glands is also severely affected
            in partially rescued embryos'
  - term:
      id: GO:0072284
      label: metanephric S-shaped body morphogenesis
    evidence_type: IGI
    original_reference_id: PMID:10101119
    review:
      summary: WT1 required for nephron morphogenesis including S-shaped body 
        stage.
      action: ACCEPT
      reason: Core kidney development function.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: 'Analysis of the observed hypoplastic kidneys demonstrate
            a continuous requirement for WT1 during nephrogenesis, in particular,
            in the formation of mature glomeruli'
  - term:
      id: GO:0061032
      label: visceral serous pericardium development
    evidence_type: IGI
    original_reference_id: PMID:10101119
    review:
      summary: WT1 is expressed in epicardium and required for its development.
      action: KEEP_AS_NON_CORE
      reason: Valid but secondary to kidney/gonad roles.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: 'WT1 is expressed in the early proepicardium, the epicardium
            and the subepicardial mesenchymal cells (SEMC)'
  - term:
      id: GO:0001658
      label: branching involved in ureteric bud morphogenesis
    evidence_type: IGI
    original_reference_id: PMID:10101119
    review:
      summary: WT1 regulates ureteric bud development.
      action: ACCEPT
      reason: Core kidney development function.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: 'a general requirement for this protein in the formation
            of organs derived from the intermediate mesoderm'
  - term:
      id: GO:0001822
      label: kidney development
    evidence_type: IGI
    original_reference_id: PMID:11912180
    review:
      summary: Reduced WT1 levels cause crescentic glomerulonephritis or 
        mesangial sclerosis depending on dosage. WT1 regulates podocyte genes 
        nphs1 and podocalyxin [PMID:11912180].
      action: ACCEPT
      reason: Core biological process. WT1 is essential for all stages of kidney
        development and podocyte maintenance.
      supported_by:
        - reference_id: PMID:11912180
          supporting_text: 'WT1 is a key regulator of podocyte function: reduced expression
            levels cause crescentic glomerulonephritis and mesangial sclerosis.'
  - term:
      id: GO:0032835
      label: glomerulus development
    evidence_type: IGI
    original_reference_id: PMID:10101119
    review:
      summary: WT1 required for mature glomeruli formation.
      action: ACCEPT
      reason: Core kidney development function.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: 'a continuous requirement for WT1 during nephrogenesis,
            in particular, in the formation of mature glomeruli'
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IGI
    original_reference_id: PMID:10101119
    review:
      summary: WT1 prevents apoptosis in developing kidney/epicardium.
      action: KEEP_AS_NON_CORE
      reason: Likely secondary to WT1's role in regulating survival genes.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: YAC complementation shows a requirement for Wt1 in 
            the development of epicardium, adrenal gland and throughout 
            nephrogenesis.
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IGI
    original_reference_id: PMID:11912180
    review:
      summary: WT1 activates podocyte-specific genes like nphs1 and podocalyxin.
      action: ACCEPT
      reason: Core function in podocyte gene regulation.
      supported_by:
        - reference_id: PMID:11912180
          supporting_text: 'WT1 is a key regulator of podocyte function: reduced expression
            levels cause crescentic glomerulonephritis and mesangial sclerosis.'
  - term:
      id: GO:0072207
      label: metanephric epithelium development
    evidence_type: IEP
    original_reference_id: PMID:7856737
    review:
      summary: WT1 expressed in developing metanephric epithelium, consistent 
        with role.
      action: ACCEPT
      reason: Expression pattern supports functional role in kidney development.
      supported_by:
        - reference_id: PMID:7856737
          supporting_text: Comparative in situ hybridization analysis of PAX2, 
            PAX8, and WT1 gene transcription in human fetal kidney and Wilms' 
            tumors.
  - term:
      id: GO:0071320
      label: cellular response to cAMP
    evidence_type: IEP
    original_reference_id: PMID:15961562
    review:
      summary: WT1 expression regulated by cAMP signaling in placenta.
      action: KEEP_AS_NON_CORE
      reason: IEP evidence only. Expression response to cAMP does not indicate 
        direct function in cAMP signaling pathway.
      supported_by:
        - reference_id: PMID:15961562
          supporting_text: Jun 16. Expression, regulation, and function of 
            paired-box gene 8 in the human placenta and placental cancer cell 
            lines.
  - term:
      id: GO:0071371
      label: cellular response to gonadotropin stimulus
    evidence_type: IDA
    original_reference_id: PMID:15961562
    review:
      summary: WT1 expression responsive to gonadotropin in placenta.
      action: KEEP_AS_NON_CORE
      reason: Placental expression context. Not a core function but reflects 
        tissue-specific regulation.
      supported_by:
        - reference_id: PMID:15961562
          supporting_text: Jun 16. Expression, regulation, and function of 
            paired-box gene 8 in the human placenta and placental cancer cell 
            lines.
  - term:
      id: GO:0008584
      label: male gonad development
    evidence_type: IEP
    original_reference_id: PMID:17848411
    review:
      summary: WT1 expressed during fetal testis development.
      action: ACCEPT
      reason: Supports core role in gonad development. Expression pattern is 
        consistent with functional requirement.
      supported_by:
        - reference_id: PMID:17848411
          supporting_text: Epub 2007 Sep 11. Developmental changes in human 
            fetal testicular cell numbers and messenger ribonucleic acid levels 
            during the second trimester.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:15961562
    review:
      summary: Nuclear localization in placental cells.
      action: ACCEPT
      reason: Consistent with nuclear localization in all tissues.
      supported_by:
        - reference_id: PMID:15961562
          supporting_text: Jun 16. Expression, regulation, and function of 
            paired-box gene 8 in the human placenta and placental cancer cell 
            lines.
  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse WT1. Well-supported by direct human evidence.
      action: ACCEPT
      reason: Human WT1 has documented transcription activator activity (IDA 
        evidence exists).
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse WT1. Core function.
      action: ACCEPT
      reason: Well-supported by human experimental evidence.
  - term:
      id: GO:2001076
      label: positive regulation of metanephric ureteric bud development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse knockout studies.
      action: ACCEPT
      reason: Consistent with human WT1's role in kidney development.
  - term:
      id: GO:0007356
      label: thorax and anterior abdomen determination
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse. This is a Drosophila-centric term.
      action: REMOVE
      reason: This GO term is specific to Drosophila body segmentation. Not 
        applicable to mammalian WT1 biology. Likely annotation error.
  - term:
      id: GO:0008406
      label: gonad development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse knockout studies. Core function.
      action: ACCEPT
      reason: Well-supported by human genetics (DDS, Frasier syndrome).
  - term:
      id: GO:0060421
      label: positive regulation of heart growth
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse. Heart involvement via epicardium.
      action: KEEP_AS_NON_CORE
      reason: Valid but secondary to kidney/gonad roles.
  - term:
      id: GO:0060539
      label: diaphragm development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse. WT1 mutations cause Meacham syndrome with 
        diaphragm defects.
      action: KEEP_AS_NON_CORE
      reason: Documented in Meacham syndrome but not core function.
  - term:
      id: GO:0072075
      label: metanephric mesenchyme development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse. Core kidney development function.
      action: ACCEPT
      reason: WT1 essential for metanephric mesenchyme development and MET.
  - term:
      id: GO:0035802
      label: adrenal cortex formation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse. Adrenal development affected in Wt1 mutants.
      action: KEEP_AS_NON_CORE
      reason: Valid but secondary developmental role.
  - term:
      id: GO:0060923
      label: cardiac muscle cell fate commitment
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse. Epicardial progenitor role.
      action: KEEP_AS_NON_CORE
      reason: Secondary to kidney/gonad functions.
  - term:
      id: GO:0001570
      label: vasculogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transfer from mouse. Related to epicardial/heart development.
      action: KEEP_AS_NON_CORE
      reason: Secondary developmental role.
  - term:
      id: GO:0001657
      label: ureteric bud development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Core kidney development function.
      action: ACCEPT
      reason: Essential for nephrogenesis.
  - term:
      id: GO:0003156
      label: regulation of animal organ formation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Generic term for developmental regulation.
      action: MARK_AS_OVER_ANNOTATED
      reason: Overly broad term. More specific terms for kidney, gonad, heart 
        development are more appropriate.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 can be cytoplasmic but primarily nuclear.
      action: KEEP_AS_NON_CORE
      reason: Minor localization compared to nucleus.
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Core function.
      action: ACCEPT
      reason: Well-supported by human evidence.
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Core function.
      action: ACCEPT
      reason: Well-supported by human evidence.
  - term:
      id: GO:0007281
      label: germ cell development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 role in germ cell development via gonad function.
      action: KEEP_AS_NON_CORE
      reason: Related to gonad development but indirect.
  - term:
      id: GO:0008380
      label: RNA splicing
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: +KTS isoform participates in RNA processing/splicing, interacting
        with RBM4 and other splicing factors [PMID:16934801].
      action: ACCEPT
      reason: Isoform-specific function of +KTS variant.
  - term:
      id: GO:0009888
      label: tissue development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Generic developmental term.
      action: MARK_AS_OVER_ANNOTATED
      reason: Too broad. More specific terms exist.
  - term:
      id: GO:0030539
      label: male genitalia development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 required for male genital development. DDS patients have 
        genital abnormalities.
      action: ACCEPT
      reason: Core function in sex development.
  - term:
      id: GO:0030855
      label: epithelial cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 drives mesenchymal-to-epithelial transition in nephrogenesis.
      action: ACCEPT
      reason: Core function in kidney development.
  - term:
      id: GO:0043010
      label: camera-type eye development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Eye involvement in WAGR syndrome includes aniridia, but that is 
        due to PAX6.
      action: REMOVE
      reason: WT1 is not the cause of eye defects in WAGR syndrome - that is due
        to contiguous deletion including PAX6. This appears to be an annotation 
        error.
  - term:
      id: GO:0060231
      label: mesenchymal to epithelial transition
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Core function in nephrogenesis. WT1 required for MET during 
        kidney development.
      action: ACCEPT
      reason: Well-documented developmental function.
  - term:
      id: GO:0072166
      label: posterior mesonephric tubule development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 required for mesonephric development.
      action: ACCEPT
      reason: Part of urogenital development.
  - term:
      id: GO:0072302
      label: negative regulation of metanephric glomerular mesangial cell 
        proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 regulates mesangial cell proliferation. Reduced WT1 causes 
        mesangial sclerosis.
      action: ACCEPT
      reason: Consistent with podocyte/glomerular function.
  - term:
      id: GO:2000020
      label: positive regulation of male gonad development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 activates SRY and promotes male gonad development.
      action: ACCEPT
      reason: Core function in sex determination.
  - term:
      id: GO:2000195
      label: negative regulation of female gonad development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 promotes male development, which indirectly suppresses female
        pathway.
      action: UNDECIDED
      reason: The relationship is complex. WT1 is required for gonad development
        of both sexes. The negative regulation of female gonad development may 
        be overstated.
  - term:
      id: GO:0072112
      label: podocyte differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: WT1 essential for podocyte differentiation and maintenance.
      action: ACCEPT
      reason: Core function. WT1 regulates podocyte-specific genes (nphs1, 
        podocalyxin) [PMID:11912180].
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9767700
    review:
      summary: Reactome pathway annotation. WT1 binds CDH1 gene promoter.
      action: ACCEPT
      reason: Consistent with nuclear localization.
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: NAS
    original_reference_id: PMID:7862533
    review:
      summary: Review article documenting WT1 as transcription factor.
      action: ACCEPT
      reason: Core function with extensive experimental support.
      supported_by:
        - reference_id: PMID:7862533
          supporting_text: High affinity binding sites for the Wilms' tumour 
            suppressor protein WT1.
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: NAS
    original_reference_id: PMID:7862533
    review:
      summary: Core function from review.
      action: ACCEPT
      reason: Well-supported.
      supported_by:
        - reference_id: PMID:7862533
          supporting_text: High affinity binding sites for the Wilms' tumour 
            suppressor protein WT1.
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: NAS
    original_reference_id: PMID:8393820
    review:
      summary: Review characterizing WT1 as transcription factor.
      action: ACCEPT
      reason: Core function.
      supported_by:
        - reference_id: PMID:8393820
          supporting_text: 'The WT1 Wilms tumor gene product: a developmentally regulated
            transcription factor in the kidney that functions as a tumor suppressor.'
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: NAS
    original_reference_id: PMID:8393820
    review:
      summary: Core function from review.
      action: ACCEPT
      reason: Well-supported.
      supported_by:
        - reference_id: PMID:8393820
          supporting_text: 'The WT1 Wilms tumor gene product: a developmentally regulated
            transcription factor in the kidney that functions as a tumor suppressor.'
  - term:
      id: GO:0003344
      label: pericardium morphogenesis
    evidence_type: TAS
    original_reference_id: PMID:10101119
    review:
      summary: WT1 is expressed in proepicardium and epicardium. Wt1 null mice 
        die at E13.5 due to heart failure from defective epicardial development.
        YAC complementation studies demonstrate continuous requirement for WT1 
        in epicardial/pericardial development.
      action: NEW
      reason: Well-supported by knockout studies showing WT1 is essential for 
        epicardial development. The epicardium is the visceral layer of the 
        pericardium.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: YAC complementation shows a requirement for Wt1 in 
            the development of epicardium, adrenal gland and throughout 
            nephrogenesis.
        - reference_id: file:human/WT1/WT1-deep-research-cyberian.md
  - term:
      id: GO:0060317
      label: cardiac epithelial to mesenchymal transition
    evidence_type: TAS
    original_reference_id: PMID:10101119
    review:
      summary: WT1 is required for epicardial epithelial-to-mesenchymal 
        transition (EMT) that generates cardiovascular progenitor cells. WT1 
        regulates epicardial EMT through Wnt/beta-catenin signaling and retinoic
        acid signaling via direct Raldh2 regulation.
      action: NEW
      reason: WT1 drives EMT in epicardium (opposite to MET in kidney), 
        generating cardiac fibroblasts, vascular smooth muscle cells, and 
        coronary endothelial cells.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: YAC complementation shows a requirement for Wt1 in 
            the development of epicardium, adrenal gland and throughout 
            nephrogenesis.
        - reference_id: file:human/WT1/WT1-deep-research-cyberian.md
  - term:
      id: GO:0060947
      label: cardiac vascular smooth muscle cell differentiation
    evidence_type: TAS
    original_reference_id: PMID:10101119
    review:
      summary: Epicardial EMT driven by WT1 generates cardiac vascular smooth 
        muscle cells that contribute to coronary vasculature formation. Wt1 null
        mice show impaired coronary plexus formation.
      action: NEW
      reason: WT1-dependent epicardial EMT produces vascular smooth muscle cells
        for coronary vessels.
      supported_by:
        - reference_id: PMID:10101119
          supporting_text: YAC complementation shows a requirement for Wt1 in 
            the development of epicardium, adrenal gland and throughout 
            nephrogenesis.
        - reference_id: file:human/WT1/WT1-deep-research-cyberian.md
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:9815658
    negated: true
    isoform: P19544-1
    review:
      summary: The +KTS isoform (P19544-1) does NOT activate transcription. 
        PMID:9815658 shows the SRY promoter was strongly activated by WT1(-KTS) 
        isoforms but was NOT activated by WT1(+KTS) isoforms. The +KTS 
        tripeptide insertion alters DNA binding capability. This is a classic 
        example of isoform-specific function where the two splice variants have 
        opposite activities.
      action: ACCEPT
      reason: Well-documented isoform-specific NOT annotation. The +KTS isoform 
        lacks transcriptional activation ability that the -KTS isoform 
        possesses, due to altered DNA binding from the KTS insertion. This is a 
        paradigm case of functional divergence between splice isoforms.
      supported_by:
        - reference_id: PMID:9815658
          supporting_text: by the WT1 isoforms without the KTS tripeptide, 
            WT1(-)KTS, but was not activated by the WT1 isoforms with the KTS 
            tripeptide, WT1(+)KTS, in all cells tested
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10101119
    title: YAC complementation shows a requirement for Wt1 in the development of
      epicardium, adrenal gland and throughout nephrogenesis.
    findings:
      - statement: WT1 expressed in proepicardium, epicardium, and subepicardial
          mesenchymal cells
        supporting_text: Using a lacZ reporter gene inserted into a YAC 
          construct, we demonstrate that WT1 is expressed in the early 
          proepicardium, the epicardium and the subepicardial mesenchymal cells 
          (SEMC).
      - statement: Wt1 null mice die at E13.5 due to heart failure
        supporting_text: Knock-out mice were shown to have defects in the 
          urogenital system and to die at embryonic day E13.5, probably due to 
          heart failure.
      - statement: Continuous requirement for WT1 during nephrogenesis
        supporting_text: Analysis of the observed hypoplastic kidneys 
          demonstrate a continuous requirement for WT1 during nephrogenesis, in 
          particular, in the formation of mature glomeruli.
      - statement: Adrenal gland development severely affected
        supporting_text: Finally, we show that the development of adrenal glands
          is also severely affected in partially rescued embryos.
  - id: PMID:11912180
    title: WT1 is a key regulator of podocyte function
    findings:
      - statement: Reduced WT1 causes crescentic glomerulonephritis or mesangial
          sclerosis
        supporting_text: we demonstrate that reduced expression levels of WT1 
          result in either crescentic glomerulonephritis or mesangial sclerosis 
          depending on the gene dosage.
      - statement: WT1 regulates nphs1 and podocalyxin expression
        supporting_text: Strikingly, the two podocyte-specific genes nphs1 and 
          podocalyxin are dramatically downregulated in mice with decreased 
          levels of Wt1, suggesting that these two genes act downstream of Wt1.
  - id: PMID:1332065
    title: Human platelet-derived growth factor A chain is transcriptionally 
      repressed by the Wilms tumor suppressor WT1.
    findings:
      - statement: WT1 represses PDGFA transcription
        supporting_text: WT1 bound to several sites in this region of the 
          promoter, as demonstrated by gel-shift analysis and DNase I 
          footprinting, and functioned as a powerful repressor of PDGF-A 
          transcription in vivo.
  - id: PMID:14701728
    title: BASP1 is a transcriptional cosuppressor for the Wilms' tumor 
      suppressor protein WT1.
    findings:
      - statement: BASP1 interacts with WT1
        supporting_text: WT1 and BASP1 associate within the nuclei of cells that
          naturally express both proteins.
      - statement: BASP1 converts WT1 from activator to repressor
        supporting_text: BASP1 can confer WT1 cosuppressor activity in 
          transfection assays, and elimination of endogenous BASP1 expression 
          augments transcriptional activation by WT1.
  - id: PMID:15518539
    title: Why zinc fingers prefer zinc
    findings:
      - statement: NMR structure of WT1 zinc fingers with zinc
  - id: PMID:15520190
    title: SUMO-1 modification of the Wilms' tumor suppressor WT1.
    findings:
      - statement: +KTS isoform localizes to nuclear speckles
      - statement: -KTS isoform has diffuse nuclear distribution
  - id: PMID:1662794
    title: Characterization of the zinc finger protein encoded by the WT1 Wilms'
      tumor locus.
    findings:
      - statement: WT1 binds EGR consensus sequence
      - statement: Nuclear localization demonstrated
  - id: PMID:16467207
    title: Wilms tumor suppressor, Wt1, is a transcriptional activator of the 
      erythropoietin gene.
    findings:
      - statement: WT1 activates EPO gene transcription
  - id: PMID:16934801
    title: WT1 interacts with the splicing protein RBM4
    findings:
      - statement: WT1 interacts with RBM4
        supporting_text: Here we show that WT1 interacts with the novel splicing
          regulator RBM4.
      - statement: +KTS isoform modulates RBM4 splicing activity
        supporting_text: We found that overexpressed WT1(+KTS) abrogated this 
          effect of RBM4 on splice-site selection, whereas WT1(-KTS) did not. We
          conclude that the (+KTS) form of WT1 is able to inhibit the effect of 
          RBM4 on alternative splicing.
      - statement: Colocalization in nuclear speckles
        supporting_text: Each protein was found to colocalize in nuclear 
          speckles and to cosediment with supraspliceosomes in glycerol 
          gradients.
  - id: PMID:23042785
    title: Control of epigenetic states by WT1 via regulation of de novo DNA 
      methyltransferase 3A.
    findings:
      - statement: WT1 transactivates DNMT3A expression
        supporting_text: We demonstrate that depletion of WT1 by 
          short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells 
          and human embryonal kidney-derived cell lines.
      - statement: WT1 recruited to DNMT3A promoter by ChIP
        supporting_text: Chromatin immunoprecipitation assays demonstrate WT1 
          recruitment to the DNMT3A promoter region and reporter assays confirm 
          that WT1 directly transactivates DNMT3A expression.
      - statement: WT1 overexpression causes promoter methylation changes
        supporting_text: Using genome-wide promoter methylation arrays, we show 
          that human embryonal kidney cells over-expressing WT1 acquire DNA 
          methylation changes at specific gene promoters where DNMT3A 
          recruitment is increased, with hypermethylation being associated with 
          silencing of gene expression.
  - id: PMID:25258363
    title: Wilms tumor protein recognizes 5-carboxylcytosine within a specific 
      DNA sequence
    findings:
      - statement: WT1 binds 5'-GCG(T/G)GGGCG-3' motif
        supporting_text: Consequently, WT1 binds the same consensus sequence as 
          Egr1/Zif268 (Stoll et al. 2007)
      - statement: High affinity for unmethylated and 5mC-containing DNA
        supporting_text: Egr1/Zif268 and WT1 showed slightly higher affinity for
          the fully methylated sequence by factors of ∼2.8 (Egr1) and ∼1.8 (WT1)
      - statement: Lower affinity for oxidized forms (5hmC, 5fC, 5caC)
        supporting_text: Both displayed high affinity for the sequence when C or
          5 mC was present and much reduced affinity when 5 hmC or 5 fC was 
          present
  - id: PMID:7585606
    title: Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor
      suppressor gene WT1.
    findings:
      - statement: WT1 represses BCL2 and MYC transcription
        supporting_text: We found that WT1 can repress transcription of both the
          bcl-2 and c-myc promoters. This suggests that WT1 regulates bcl-2 and 
          c-myc during renal development, and the loss of functional WT1 results
          in deregulation of bcl-2 and c-myc, contributing to tumor formation.
  - id: PMID:7720589
    title: Repression of Pax-2 by WT1 during normal kidney development.
    findings:
      - statement: WT1 binds PAX2 promoter elements
        supporting_text: Binding of WT1 to three high affinity sites in the 5' 
          untranslated Pax-2 leader sequence was demonstrated by DNAseI 
          footprinting analysis.
      - statement: WT1-dependent transcriptional repression of PAX2
        supporting_text: Furthermore, co-transfection assays using CAT reporter 
          constructs under the control of Pax-2 regulatory sequences 
          demonstrated WT1-dependent transcriptional repression.
  - id: PMID:7862533
    title: High affinity binding sites for the Wilms' tumour suppressor protein 
      WT1.
    findings:
      - statement: Characterized WT1 DNA-binding consensus
  - id: PMID:8119964
    title: WT1 is negatively autoregulated
    findings:
      - statement: WT1 represses its own transcription
      - statement: WT1 homodimerization via zinc fingers
  - id: PMID:8393820
    title: 'The WT1 Wilms tumor gene product: a developmentally regulated transcription
      factor in the kidney that functions as a tumor suppressor.'
    findings:
      - statement: Review of WT1 function in development and cancer
  - id: PMID:9553041
    title: Inhibition of cellular proliferation by the Wilms tumor suppressor 
      WT1 requires association with the inducible chaperone Hsp70.
    findings:
      - statement: WT1 interacts with Hsp70
        supporting_text: By immunoprecipitation and protein microsequencing 
          analysis, we have identified a major cellular protein associated with 
          endogenous WT1 to be the inducible chaperone Hsp70.
      - statement: Hsp70 required for WT1 antiproliferative function
        supporting_text: These observations indicate that Hsp70 is an important 
          cofactor for the function of WT1, and suggest a potential role for 
          this chaperone during kidney differentiation.
      - statement: WT1 localizes to nuclear speckles
        supporting_text: Hsp70 is recruited to the characteristic subnuclear 
          clusters that contain WT1.
  - id: PMID:9815658
    title: 'The Wilms'' tumor gene WT1 can regulate genes involved in sex determination
      and differentiation: SRY, Müllerian-inhibiting substance, and the androgen receptor.'
    findings:
      - statement: WT1 activates SRY promoter
        supporting_text: SRY (the sex-determining region of the Y chromosome) 
          promoter was strongly activated by the WT1 isoforms without the KTS 
          tripeptide, WT1(-)KTS, but was not activated by the WT1 isoforms with 
          the KTS tripeptide, WT1(+)KTS, in all cells tested.
      - statement: WT1 represses MIS and androgen receptor
        supporting_text: The MüAdullerian-inhibiting substance (MIS) promoter 
          was strongly repressed by WT1(-)KTS isoforms and more weakly repressed
          by the WT1(+)KTS isoforms in Sertoli cells but not in HeLa cells.
      - statement: Isoform-specific effects (-KTS vs +KTS)
        supporting_text: The second alternative splicing site, which inserts the
          tripeptide KTS, alters the DNA binding capability.
  - id: PMID:19447967
    title: Shifted Transversal Design smart-pooling for high coverage 
      interactome mapping.
    findings: []
  - id: PMID:21900206
    title: A directed protein interaction network for investigating 
      intracellular signal transduction.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:25601757
    title: WT1 recruits TET2 to regulate its target gene expression and suppress
      leukemia cell proliferation.
    findings: []
  - id: PMID:27229929
    title: Systematic interactome mapping of acute lymphoblastic leukemia cancer
      gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common 
      interactor.
    findings: []
  - id: PMID:31515488
    title: Extensive disruption of protein interactions by genetic variants 
      across the allele frequency spectrum in human populations.
    findings: []
  - id: PMID:21390327
    title: PINCH1 is transcriptional regulator in podocytes that interacts with 
      WT1 and represses podocalyxin expression.
    findings:
      - statement: PINCH1 interacts with WT1 via LIM1 domain and zinc-finger 
          domain
  - id: PMID:9178767
    title: Differential regulation of the human Wilms tumour suppressor gene 
      (WT1) promoter by two isoforms of PAX2.
    findings: []
  - id: PMID:8132626
    title: Transcriptional regulation of the human Wilms' tumor gene (WT1). Cell
      type-specific enhancer and promiscuous promoter.
    findings: []
  - id: PMID:7588596
    title: WT1 suppresses synthesis of the epidermal growth factor receptor and 
      induces apoptosis.
    findings:
      - statement: WT1 represses PDGF-A transcription
  - id: PMID:19050011
    title: Dynamic interaction between WT1 and BASP1 in transcriptional 
      regulation during differentiation.
    findings: []
  - id: PMID:9765217
    title: Induction of Rb-associated protein (RbAp46) by Wilms' tumor 
      suppressor WT1 mediates growth inhibition.
    findings:
      - statement: WT1 inhibits cell proliferation
  - id: PMID:8306891
    title: Nuclear localization of the protein encoded by the Wilms' tumor gene 
      WT1 in embryonic and adult tissues.
    findings:
      - statement: WT1 localizes to nucleus
  - id: PMID:12802290
    title: 'Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative
      transcriptional targets using cDNA microarray expression profiling of genetically
      defined Wilms'' tumors.'
    findings: []
  - id: PMID:19205749
    title: Membranoproliferative glomerulonephritis associated with a mutation 
      in Wilms' tumour suppressor gene 1.
    findings:
      - statement: WT1 role in glomerular basement membrane development
  - id: PMID:7856737
    title: Comparative in situ hybridization analysis of PAX2, PAX8, and WT1 
      gene transcription in human fetal kidney and Wilms' tumors.
    findings:
      - statement: WT1 expression during kidney development
  - id: PMID:15961562
    title: Expression, regulation, and function of paired-box gene 8 in the 
      human placenta and placental cancer cell lines.
    findings:
      - statement: WT1 response to gonadotropin stimulus
      - statement: WT1 response to cAMP
  - id: PMID:17848411
    title: Developmental changes in human fetal testicular cell numbers and 
      messenger ribonucleic acid levels during the second trimester.
    findings:
      - statement: WT1 expression in male gonad development
  - id: Reactome:R-HSA-9767700
    title: Reactome pathway annotation
    findings: []
  - id: file:human/WT1/WT1-deep-research-falcon.md
    title: Deep research report (falcon provider) - WT1 functional annotation
    findings:
      - statement: WT1 contains four C2H2 zinc fingers mediating high-affinity 
          binding to GC-rich motifs such as 5'-GCG(T/G)GGGCG-3' in target 
          promoters/enhancers
        supporting_text: 'Domain architecture and nucleic-acid interactions: WT1 contains
          four C2H2 zinc fingers (exons 7-10) mediating high-affinity binding to GC-rich
          motifs such as 5''-GCG(T/G)GGGCG-3'' in target promoters/enhancers'
      - statement: The -KTS isoform binds DNA sequence-specifically and drives 
          transcriptional programs, while +KTS shows low DNA affinity and has 
          RNA-binding/processing roles
        supporting_text: The -KTS isoform binds DNA sequence-specifically and 
          drives transcriptional programs, whereas the +KTS isoform shows low 
          DNA affinity, associates with spliceosomal components, and has 
          RNA-binding/processing roles
      - statement: WT1(+KTS) co-localizes with splicing speckles and interacts 
          with splicing factors U2AF65 and WTAP
        supporting_text: WT1(+KTS) co-localizes with splicing speckles, 
          interacts with splicing factors (U2AF65, WTAP), forms complexes with 
          ZNF255 and BASP1 that participate in RNA maturation
      - statement: WT1 is essential for nephron development and adult podocyte 
          integrity
        supporting_text: 'Nephrogenesis and podocyte maintenance: WT1 binds and regulates
          kidney lineage and podocyte genes and is essential for nephron development
          and adult podocyte integrity'
      - statement: WT1 mRNA is overexpressed in >80% of AML and used for MRD 
          monitoring
        supporting_text: WT1 mRNA is overexpressed in >80% of AML; standardized 
          ELN qRT-PCR thresholds are widely used for MRD risk stratification and
          post-transplant surveillance
  - id: file:human/WT1/WT1-deep-research-cyberian.md
    title: Deep research report (cyberian provider) - WT1 comprehensive 
      functional analysis
    findings:
      - statement: WT1 zinc fingers 2-4 insert into major groove for 
          base-specific DNA contacts; ZnF1 amplifies affinity without 
          contributing to sequence specificity
        supporting_text: The second, third, and fourth zinc finger domains 
          insert deep into the major groove of DNA where they make base-specific
          contacts. Zinc fingers 2 and 3 are primarily responsible for most of 
          the binding affinity and can function as a minimal DNA binding domain,
          while zinc finger 4 is indispensable for target specificity
      - statement: WT1-DNA binding has Kd of 1.14 x 10^-9 M and is 
          entropy-driven, unlike EGR1
        supporting_text: Quantitative binding studies have demonstrated that 
          recombinant WT1 zinc fingers bind to the dodecamer DNA sequence 
          GCG-TGG-GCG-TGT with high affinity, exhibiting a dissociation constant
          (Kd) of 1.14 x 10^-9 M under physiological conditions. Thermodynamic 
          analysis revealed that WT1-DNA interaction is an entropy-driven 
          process
      - statement: KTS insertion increases linker flexibility between ZnF3-4, 
          abolishing ZnF4 DNA contact
        supporting_text: The molecular basis for the functional differences 
          between +KTS and -KTS isoforms was elucidated by NMR structural 
          studies demonstrating that the KTS insertion increases the flexibility
          of the linker between fingers 3 and 4, abrogating the binding of the 
          fourth zinc finger to its cognate site in the DNA major groove
      - statement: Normal +KTS/-KTS ratio is 2:1; Frasier syndrome results from 
          altered ratio to 1:2
        supporting_text: The physiological importance of maintaining the correct
          ratio of +KTS to -KTS isoforms (normally approximately 2:1) is 
          dramatically illustrated by Frasier syndrome, in which mutations 
          disrupting the +KTS splice site alter this ratio to 1:2
      - statement: p53 interaction converts WT1 from repressor to activator; WT1
          stabilizes p53 protein
        supporting_text: In the absence of p53, WT1 functions as a potent 
          transcriptional activator of EGR1-like promoter sequences rather than 
          as a repressor. WT1 expression can stabilize p53 protein, enhance its 
          DNA binding to target sequences
      - statement: BASP1 myristoylation recruits PIP2 to promoters, enabling 
          HDAC1-mediated repression
        supporting_text: Mechanistically, myristoylated BASP1 binds to nuclear 
          phosphatidylinositol 4,5-bisphosphate (PIP2), which leads to the 
          recruitment of PIP2 to the promoter regions of WT1-dependent target 
          genes. This association with PIP2 is required for the interaction of 
          BASP1 with histone deacetylase 1 (HDAC1), enabling chromatin 
          deacetylation and gene silencing
      - statement: WT1 directly activates nephrin (NPHS1) transcription >10-fold
          via specific promoter element
        supporting_text: WT1 binds to a specific responsive element in the 
          nephrin promoter and activates transcription more than 10-fold. 
          Transgenic mouse analysis confirmed that this WT1 binding site is 
          required for podocyte-specific nephrin expression in vivo
      - statement: WT1 directly activates SF1 and SRY in gonad development; DDS 
          mutations fail to activate SRY
        supporting_text: The -KTS isoform of WT1, but not the +KTS form, 
          directly binds to and transactivates the Sf1 promoter through four 
          identified binding sites. WT1 also directly regulates the 
          sex-determining gene SRY by activating its expression. Mutant WT1 
          proteins found in Denys-Drash syndrome patients fail to activate the 
          SRY promoter
      - statement: WT1 required for epicardial EMT in heart development via 
          Wnt/beta-catenin and retinoic acid pathways
        supporting_text: WT1 is expressed in the proepicardium and developing 
          epicardium, where it is required for epithelial-to-mesenchymal 
          transition (EMT) that generates cardiovascular progenitor cells. WT1 
          regulates epicardial EMT through multiple signaling pathways including
          canonical Wnt/beta-catenin signaling and retinoic acid signaling 
          through direct regulation of Raldh2 expression
      - statement: WT1 ZnF1 is more important for RNA binding than DNA binding; 
          +KTS and -KTS bind RNA similarly
        supporting_text: While zinc fingers 2, 3, and 4 are required for 
          high-affinity DNA binding, zinc finger 1—which is dispensable for DNA 
          binding—is more important for RNA binding. Consequently, the KTS 
          insertion has minimal effect on RNA affinity
core_functions:
  - description: Sequence-specific DNA-binding transcription factor (-KTS 
      isoform) that regulates kidney development by activating podocyte-specific
      genes (nphs1, podocalyxin) and repressing PAX2 during 
      mesenchymal-to-epithelial transition. Binds the 5'-GCG(T/G)GGGCG-3' 
      consensus motif via C2H2 zinc fingers.
    molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    directly_involved_in:
      - id: GO:0001822
        label: kidney development
      - id: GO:0072112
        label: podocyte differentiation
      - id: GO:0060231
        label: mesenchymal to epithelial transition
    locations:
      - id: GO:0005654
        label: nucleoplasm
    anatomical_locations:
      - id: UBERON:0000074
        label: renal glomerulus
      - id: UBERON:0002113
        label: kidney
  - description: Transcription factor (-KTS isoform) that regulates gonad 
      development and sex determination by activating SRY and regulating MIS/AMH
      and androgen receptor expression. Isoform-specific activity is critical as
      Frasier syndrome results from splice site mutations altering +KTS/-KTS 
      ratio.
    molecular_function:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase 
        II-specific
    directly_involved_in:
      - id: GO:0007530
        label: sex determination
      - id: GO:0008406
        label: gonad development
    locations:
      - id: GO:0005654
        label: nucleoplasm
    anatomical_locations:
      - id: UBERON:0000473
        label: testis
      - id: UBERON:0000992
        label: ovary
  - description: Transcriptional repressor (-KTS isoform) that suppresses cell 
      proliferation by repressing growth-promoting genes including BCL2, MYC, 
      PDGFA, and EGFR. Growth suppression requires Hsp70 association. 
      Loss-of-function mutations cause Wilms tumor.
    molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    directly_involved_in:
      - id: GO:0008285
        label: negative regulation of cell population proliferation
      - id: GO:0000122
        label: negative regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0005654
        label: nucleoplasm
  - description: RNA-binding protein (+KTS isoform) that participates in 
      post-transcriptional regulation. Localizes to nuclear speckles where it 
      interacts with splicing factors (U2AF65, RBM4) and modulates alternative 
      splicing. ZnF1 is more important for RNA binding than DNA binding. The 
      +KTS isoform has reduced DNA-binding affinity due to the three amino acid 
      insertion between zinc fingers 3 and 4 which increases linker flexibility 
      and abolishes ZnF4 DNA contact.
    molecular_function:
      id: GO:0003723
      label: RNA binding
    directly_involved_in:
      - id: GO:0008380
        label: RNA splicing
    locations:
      - id: GO:0016607
        label: nuclear speck
  - description: Transcription factor required for epicardial 
      epithelial-to-mesenchymal transition (EMT) during heart development. 
      Expressed in proepicardium and epicardium, WT1 regulates EMT through 
      Wnt/beta-catenin signaling (via Lef1, Ctnnb1), non-canonical Wnt5a 
      signaling, and retinoic acid signaling (via direct Raldh2 regulation). 
      Epicardial EMT generates cardiac fibroblasts, vascular smooth muscle 
      cells, and coronary endothelial cells. WT1 null embryos die at E13.5 due 
      to heart failure from defective epicardium.
    molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    directly_involved_in:
      - id: GO:0003344
        label: pericardium morphogenesis
      - id: GO:0060317
        label: cardiac epithelial to mesenchymal transition
      - id: GO:0060947
        label: cardiac vascular smooth muscle cell differentiation
    locations:
      - id: GO:0005654
        label: nucleoplasm
    anatomical_locations:
      - id: UBERON:0002348
        label: epicardium
      - id: UBERON:0000948
        label: heart
    supported_by:
      - reference_id: PMID:10101119
      - reference_id: file:human/WT1/WT1-deep-research-cyberian.md
proposed_new_terms: []
suggested_questions:
  - question: What is the precise mechanism by which WT1 switches between 
      activator and repressor function?
  - question: What are the distinct RNA targets of the +KTS isoform?
suggested_experiments:
  - description: ChIP-seq for WT1 isoforms to systematically identify 
      genome-wide binding sites for -KTS vs +KTS isoforms, which would clarify 
      their distinct transcriptional targets.
  - description: CLIP-seq for +KTS isoform to identify RNA binding targets, 
      which would elucidate its post-transcriptional regulatory functions.