EGR2

id: P11161
gene_symbol: EGR2
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  EGR2 (also known as Krox-20) is a C2H2-type zinc finger transcription factor belonging to the
  early growth response (EGR) family. Its primary, best-characterized function is as a master
  transcriptional regulator of myelination in Schwann cells of the peripheral nervous system,
  where it activates myelin structural genes (MPZ, PMP22, GJB1, MAG) in cooperation with SOX10.
  EGR2 binds GC-rich consensus DNA sequences through three C2H2 zinc finger domains and recruits
  the corepressors NAB1 and NAB2 to modulate transcriptional output. It also has an experimentally
  demonstrated E3 SUMO ligase activity, catalyzing SUMO1 conjugation to its own NAB coregulators
  via interaction with UBC9 (PMID:21836637). EGR2 plays critical roles in hindbrain segmentation
  (specifying rhombomeres 3 and 5 through regulation of HOX genes) and in immune tolerance
  (T cell anergy, NK cell dysfunction). Mutations in EGR2, particularly in the zinc finger domains,
  cause Charcot-Marie-Tooth disease type 1D, Dejerine-Sottas syndrome, and congenital
  hypomyelinating neuropathy.
alternative_products:
- name: Long
  id: P11161-1
- name: Short
  id: P11161-2
  sequence_note: VSP_006863
existing_annotations:
# ===== IBA 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: >-
      EGR2 is a well-established C2H2 zinc finger transcription factor that binds specific
      GC-rich cis-regulatory sequences in RNA pol II-transcribed genes. IBA annotation supported
      by phylogenetic inference across the EGR/Krox/Sp family is consistent with extensive
      experimental evidence (PMID:17717711, PMID:12687019, PMID:28473536).
    action: ACCEPT
    reason: >-
      Core molecular function of EGR2 as a sequence-specific DNA-binding TF. EGR2 binds
      GC-rich EGR consensus sites (e.g. 5'-GCGGGGGCG-3') via its zinc fingers. This IBA
      annotation is well supported by direct experimental evidence from multiple studies.
    additional_reference_ids:
      - file:human/EGR2/EGR2-deep-research-falcon.md
    supported_by:
      - reference_id: PMID:9537424
        supporting_text: >-
          Egr2, (also known as Krox20) ... encoding a protein that binds DNA in a
          sequence-specific manner and acts as a transcription factor
      - reference_id: PMID:14532282
        supporting_text: >-
          Krox20, a zinc finger transcription factor required for Schwann cell differentiation
- 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: >-
      EGR2/Krox-20 is a bona fide DNA-binding transcription factor that activates RNA polymerase
      II-dependent transcription of target genes including myelin genes and HOX genes. IBA
      annotation well supported phylogenetically and experimentally.
    action: ACCEPT
    reason: >-
      Core molecular function. EGR2 directly binds DNA and activates pol II transcription.
      This is the primary molecular function of EGR2 and is supported by IDA evidence from
      PMID:17717711 and PMID:12687019, as well as the TFClass database annotation.
    supported_by:
      - reference_id: PMID:17717711
        supporting_text: >-
          Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and
          related inherited peripheral neuropathies
      - reference_id: PMID:14532282
        supporting_text: >-
          Krox20, a zinc finger transcription factor required for Schwann cell differentiation,
          ... showed a strong requirement for functional HCF-1 to activate transcription
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      EGR2 functions as a nuclear transcription factor. IBA annotation is fully consistent
      with UniProt subcellular localization and all functional evidence placing EGR2 in the
      nucleus where it binds DNA and regulates transcription.
    action: ACCEPT
    reason: >-
      Core localization. EGR2 is a nuclear TF. UniProt states "Nucleus" as subcellular location.
      All evidence from functional studies and the Reactome pathway annotations place EGR2
      in the nucleoplasm.
    supported_by:
      - reference_id: PMID:14532282
        supporting_text: >-
          Krox20, a zinc finger transcription factor required for Schwann cell differentiation
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      EGR2 is directly involved in regulation of RNA pol II transcription. This IBA annotation
      at a general level captures the core biological process role of EGR2 as a transcription
      factor. More specific annotations (positive regulation) are also present.
    action: ACCEPT
    reason: >-
      Core biological process. EGR2 regulates pol II transcription of myelin genes (MPZ, PMP22,
      GJB1, MAG), HOX genes, BNIP3L/BAK (PMID:12687019), and lipid biosynthesis genes.
      This broad term is appropriate for the IBA level.
    supported_by:
      - reference_id: PMID:12687019
        supporting_text: >-
          EGR2 could induce apoptosis in a large proportion of these lines ... EGR2 directly
          transactivates expression of BNIP3L and BAK

# ===== IEA annotations =====
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for DNA binding based on UniProt keyword mapping. EGR2 has three C2H2
      zinc finger domains that mediate sequence-specific DNA binding. This is a broad parent
      term of the more specific cis-regulatory region binding terms.
    action: ACCEPT
    reason: >-
      Correct but general. More specific terms (GO:0000978, GO:1990837) are also annotated.
      This IEA is acceptable as a broader annotation consistent with the more specific
      experimental evidence.
    supported_by:
      - reference_id: PMID:9537424
        supporting_text: >-
          encoding a protein that binds DNA in a sequence-specific manner
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for nucleus based on combined automated methods including ortholog
      mapping from mouse Egr2. Consistent with all other evidence.
    action: ACCEPT
    reason: >-
      Correct. Duplicates the IBA annotation but with different evidence code. EGR2 is a nuclear
      protein.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for nucleoplasm from ARBA machine learning. Consistent with EGR2 being
      a nuclear transcription factor. Also supported by multiple Reactome TAS annotations
      for nucleoplasm.
    action: ACCEPT
    reason: >-
      Correct. As a nuclear transcription factor, EGR2 functions in the nucleoplasm.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation based on UniProt keyword "Zinc". EGR2 contains three C2H2-type zinc
      finger domains (residues 340-364, 370-392, 398-420) that coordinate zinc ions for
      structural integrity and DNA binding.
    action: ACCEPT
    reason: >-
      Correct. The three C2H2 zinc fingers are structurally essential for EGR2 DNA-binding
      function. Disease-causing mutations cluster in these zinc finger domains.
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation based on UniProt keyword "Transferase". This reflects the E3 SUMO ligase
      activity of EGR2, which catalyzes transfer of SUMO1 to NAB1/NAB2 (PMID:21836637).
      The term is very broad.
    action: ACCEPT
    reason: >-
      Technically correct as a parent term of SUMO ligase activity (GO:0061665). The
      SUMO transferase activity is a child of transferase activity. While broad, this IEA
      mapping from the Transferase keyword is acceptable.
    supported_by:
      - reference_id: PMID:21836637
        supporting_text: >-
          we show that Krox20 functions as a SUMO ligase for its coregulators--the Nab
          proteins
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation based on UniProt keyword "Metal-binding". Broad parent of zinc ion
      binding.
    action: ACCEPT
    reason: >-
      Correct but very general. The more specific GO:0008270 (zinc ion binding) is also
      annotated. Acceptable as an IEA parent annotation.
- term:
    id: GO:0000976
    label: transcription cis-regulatory region binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara ortholog transfer (from mouse Egr2). EGR2 binds
      cis-regulatory regions in target gene promoters and enhancers. Consistent with more
      specific annotations.
    action: ACCEPT
    reason: >-
      Correct. Parent term of the more specific GO:0000978. EGR2 binds cis-regulatory elements
      of myelin genes, HOX genes, and other targets.
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. Duplicates the IBA annotation. Consistent with
      experimental evidence.
    action: ACCEPT
    reason: >-
      Correct. Duplicates IBA and IDA annotations for the same term. Acceptable.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. Duplicates the IBA and IDA annotations for this
      core function.
    action: ACCEPT
    reason: >-
      Correct. Same core function captured by higher-quality evidence codes.
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 binds chromatin at specific regulatory
      elements. This is consistent with its role as a transcription factor that binds DNA
      in a chromatin context.
    action: ACCEPT
    reason: >-
      Reasonable. As a TF that binds cis-regulatory elements in vivo, EGR2 necessarily
      interacts with chromatin. Also supported by ISS annotation from the same term.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. Parent term of the more specific pol II-specific
      annotation. Consistent with all evidence.
    action: ACCEPT
    reason: >-
      Correct. Broader parent of GO:0000981. Also annotated with IDA (PMID:14532282).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara for cytoplasmic localization. EGR2 is primarily
      nuclear, but some evidence from mouse orthologs suggests transient cytoplasmic presence,
      possibly related to nuclear export. UniProt annotates nuclear export for the mouse
      ortholog.
    action: KEEP_AS_NON_CORE
    reason: >-
      EGR2 is primarily a nuclear protein. Cytoplasmic localization may reflect transient
      shuttling or the protein before nuclear import, but this is not the primary site of
      function. Keeping as non-core.
- term:
    id: GO:0006611
    label: protein export from nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara for nuclear export. This is transferred from mouse
      Egr2 where there is ISS-level evidence. Nuclear export may relate to regulation of EGR2
      activity or turnover.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not a core function. EGR2 activity is fundamentally nuclear. Nuclear export may be a
      regulatory mechanism but is not well characterized for human EGR2. Keeping as non-core.
- term:
    id: GO:0014040
    label: positive regulation of Schwann cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 is a master regulator of Schwann cell
      myelination and promotes Schwann cell differentiation to the myelinating state. This
      is one of the best-characterized functions of EGR2.
    action: ACCEPT
    reason: >-
      Core biological process. EGR2/Krox-20 knockout mice show a block in Schwann cell
      differentiation. EGR2 mutations in humans cause demyelinating neuropathies. Also
      supported by ISS annotation.
    supported_by:
      - reference_id: PMID:9537424
        supporting_text: >-
          Stable expression of Egr2 is specifically associated with the onset of myelination
          in the peripheral nervous system (PNS). Egr2(-/-) mice display disrupted hindbrain
          segmentation and development, and a block of Schwann-cell differentiation at an
          early stage
- term:
    id: GO:0016925
    label: protein sumoylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation from combined automated methods. EGR2 functions as an E3 SUMO ligase
      for NAB1/NAB2 coregulators (PMID:21836637). The protein sumoylation process annotation
      is consistent with this enzymatic activity.
    action: ACCEPT
    reason: >-
      Correct. EGR2 catalyzes SUMO1 conjugation to NAB proteins. This is an experimentally
      validated function (PMID:21836637) and is appropriately reflected in this process
      annotation.
    supported_by:
      - reference_id: PMID:21836637
        supporting_text: >-
          Krox20 functions as a SUMO ligase for its coregulators--the Nab proteins--and that
          Nab sumoylation negatively modulates Krox20 transcriptional activity in vivo
- term:
    id: GO:0021612
    label: facial nerve structural organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 is expressed in rhombomeres 3 and 5 during
      hindbrain development, and Egr2 knockout mice show defects in cranial nerve organization
      including the facial nerve.
    action: KEEP_AS_NON_CORE
    reason: >-
      Developmental role. EGR2 regulates hindbrain segmentation and thereby influences cranial
      nerve patterning, including the facial nerve. This is a downstream developmental
      consequence rather than a direct molecular function. Keeping as non-core.
    supported_by:
      - reference_id: PMID:17717711
        supporting_text: >-
          respiratory compromise and cranial nerve dysfunction are commonly associated with
          EGR2 mutations
- term:
    id: GO:0021659
    label: rhombomere 3 structural organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2/Krox-20 is specifically expressed in
      rhombomeres 3 and 5 and is required for their proper specification. This is a core
      developmental function of EGR2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Important developmental function. EGR2 specifies odd rhombomeres by controlling HOX
      gene expression. This is a well-established role from Egr2 knockout studies but
      represents a developmental consequence of its TF activity rather than a direct molecular
      function. Keeping as non-core because it is a downstream developmental process.
- term:
    id: GO:0021665
    label: rhombomere 5 structural organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. Like rhombomere 3, EGR2 is also required for
      rhombomere 5 organization during hindbrain development.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same rationale as rhombomere 3 organization. Well-established developmental role but
      downstream of core TF activity.
- term:
    id: GO:0031643
    label: positive regulation of myelination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 is a master positive regulator of peripheral
      myelination, activating myelin gene expression.
    action: ACCEPT
    reason: >-
      Core biological process function. EGR2 is the key transcription factor driving peripheral
      myelination. Its loss causes demyelinating neuropathies. Also supported by ISS annotation.
    supported_by:
      - reference_id: PMID:9537424
        supporting_text: >-
          Stable expression of Egr2 is specifically associated with the onset of myelination
          in the peripheral nervous system
- term:
    id: GO:0035904
    label: aorta development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 has been implicated in vascular smooth
      muscle and aorta development in mouse knockout studies, but this is not a well-characterized
      function for human EGR2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peripheral function. EGR2 expression is induced by growth factors and may play roles
      in multiple tissues including vasculature, but this is not a core function. Mouse
      knockout evidence is the primary support. Keeping as non-core.
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 binds specific GC-rich DNA consensus sequences
      through its zinc finger domains.
    action: ACCEPT
    reason: >-
      Correct. Parent of more specific terms. Also annotated with IDA (PMID:17717711).
- term:
    id: GO:0045444
    label: fat cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. Mouse Egr2 has been implicated in adipogenesis,
      possibly through regulation of CEBPB. This is a secondary function for the human ortholog.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peripheral function. While EGR2 may play a role in adipocyte differentiation (UniProt
      mentions this by similarity), this is not a core function. The primary roles are in
      myelination and hindbrain development.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 positively regulates transcription of
      target genes. Consistent with its role as a transcriptional activator.
    action: ACCEPT
    reason: >-
      Correct. EGR2 is primarily a transcriptional activator. This is a broad parent of the
      more specific pol II-specific positive regulation terms.
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 interacts with other transcription factors
      and coregulators, including HCFC1 (PMID:14532282), NAB1/NAB2, and SOX10.
    action: ACCEPT
    reason: >-
      Correct. EGR2 binds to other TF-related proteins. HCFC1 interaction is experimentally
      validated (PMID:14532282). NAB1/NAB2 interactions are central to EGR2 function.
    supported_by:
      - reference_id: PMID:14532282
        supporting_text: >-
          Krox20, a zinc finger transcription factor required for Schwann cell differentiation,
          and E2F4, a cell cycle regulator, showed a strong requirement for functional HCF-1
          to activate transcription
- term:
    id: GO:0061665
    label: SUMO ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation from Ensembl Compara. EGR2 has experimentally demonstrated E3 SUMO
      ligase activity (PMID:21836637), catalyzing SUMO1 conjugation to NAB coregulators.
    action: ACCEPT
    reason: >-
      Correct. SUMO ligase activity is experimentally validated. EGR2 interacts with UBC9
      and facilitates SUMO transfer to NAB1/NAB2. Also annotated with ISS evidence.
    supported_by:
      - reference_id: PMID:21836637
        supporting_text: >-
          Krox20 functions as a SUMO ligase for its coregulators--the Nab proteins

# ===== IDA annotations =====
- term:
    id: GO:1990837
    label: sequence-specific double-stranded DNA binding
  evidence_type: IDA
  original_reference_id: PMID:28473536
  review:
    summary: >-
      IDA annotation from a systematic high-throughput SELEX study (Yin et al. 2017) that
      characterized DNA binding specificities of 542 human TFs. EGR2 was among the TFs
      analyzed for binding to both unmethylated and CpG-methylated DNA.
    action: ACCEPT
    reason: >-
      Well-supported by high-throughput systematic analysis of TF binding specificities. EGR2
      binds dsDNA in a sequence-specific manner through its C2H2 zinc fingers. The SELEX
      assay directly measures dsDNA binding.
    supported_by:
      - reference_id: PMID:28473536
        supporting_text: >-
          By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution
          of ligands by exponential enrichment), we found that there are also many TFs
          that prefer CpG-methylated sequences

# ===== ISS annotations =====
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2 (P08152). EGR2 positively regulates pol II
      transcription. Also supported by IDA annotations from PMID:17717711 and PMID:12687019.
    action: ACCEPT
    reason: >-
      Core function. ISS is consistent with IDA evidence from the same gene product.
- term:
    id: GO:0014037
    label: Schwann cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. EGR2 is essential for Schwann cell
      differentiation from the premyelinating to myelinating state.
    action: ACCEPT
    reason: >-
      Core biological process. Egr2 knockout mice show a complete block in Schwann cell
      differentiation. Human EGR2 mutations cause demyelinating neuropathies confirming
      this conserved function.
    supported_by:
      - reference_id: PMID:9537424
        supporting_text: >-
          Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a
          block of Schwann-cell differentiation at an early stage
- term:
    id: GO:0014040
    label: positive regulation of Schwann cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. EGR2 positively drives Schwann cell
      differentiation toward the myelinating phenotype.
    action: ACCEPT
    reason: >-
      Core function. Duplicates the IEA annotation with higher-quality ISS evidence.
- term:
    id: GO:0021612
    label: facial nerve structural organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. EGR2 is required for proper facial nerve
      patterning during hindbrain development.
    action: KEEP_AS_NON_CORE
    reason: >-
      Developmental consequence. Consistent with IEA annotation. Cranial nerve dysfunction
      is a clinical feature of EGR2 mutations (PMID:17717711).
    supported_by:
      - reference_id: PMID:17717711
        supporting_text: >-
          respiratory compromise and cranial nerve dysfunction are commonly associated with
          EGR2 mutations
- term:
    id: GO:0021659
    label: rhombomere 3 structural organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. Egr2 is expressed in r3 and r5 and is
      required for their specification.
    action: KEEP_AS_NON_CORE
    reason: >-
      Developmental process. Duplicates IEA annotation with higher-quality ISS evidence.
      EGR2 specifies rhombomere identity through HOX gene regulation.
- term:
    id: GO:0021665
    label: rhombomere 5 structural organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. Same rationale as rhombomere 3.
    action: KEEP_AS_NON_CORE
    reason: >-
      Developmental process. Consistent with EGR2 expression in r5 and its role in hindbrain
      segmentation.
- term:
    id: GO:0031643
    label: positive regulation of myelination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. EGR2 is the master positive regulator of
      peripheral myelination.
    action: ACCEPT
    reason: >-
      Core function. Duplicates IEA annotation with higher-quality ISS evidence.
- term:
    id: GO:0035914
    label: skeletal muscle cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. There is some evidence from mouse studies
      for EGR2 involvement in jaw opener musculature development, but this is not well
      characterized for human EGR2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peripheral function. UniProt mentions a role in jaw opener musculature development by
      similarity. This is not a core function and evidence in human is limited.

# ===== IDA annotations from PMID:17717711 =====
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:17717711
  review:
    summary: >-
      IDA annotation based on Szigeti et al. 2007, which characterized EGR2 mutations
      functionally, demonstrating that wild-type EGR2 has DNA-binding transcription factor
      activity and that disease mutations abolish this activity.
    action: ACCEPT
    reason: >-
      Core molecular function supported by direct assay. The R359W and E412K mutations
      caused loss of DNA binding and transactivation activity, confirming WT EGR2 has this
      function.
    supported_by:
      - reference_id: PMID:17717711
        supporting_text: >-
          Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and
          related inherited peripheral neuropathies
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:17717711
  review:
    summary: >-
      IDA annotation from functional characterization of EGR2 mutations. Disease mutations
      in zinc finger domains abolished sequence-specific DNA binding, confirming wild-type
      EGR2 binds DNA in a sequence-specific manner.
    action: ACCEPT
    reason: >-
      Core molecular function. Direct assay evidence from functional studies of disease variants.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:17717711
  review:
    summary: >-
      IDA annotation from functional characterization of EGR2. Wild-type EGR2 activates
      pol II transcription; disease mutations cause loss of transactivation activity.
    action: ACCEPT
    reason: >-
      Core function. Disease mutations (R359W, E412K) lost transactivation activity, confirming
      WT EGR2 positively regulates pol II transcription.

# ===== ISA annotations =====
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: >-
      ISA annotation from TFClass database (tfclass:2.3.1, C2H2 zinc finger factors).
      As a DNA-binding transcription factor, EGR2 localizes to chromatin at its target sites.
    action: ACCEPT
    reason: >-
      Reasonable. TF annotation from TFClass. EGR2 binds to chromatin at cis-regulatory
      elements of target genes.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: >-
      ISA annotation from TFClass database classification of EGR2 as a C2H2 zinc finger
      transcription factor (class 2.3.1).
    action: ACCEPT
    reason: >-
      Core function. TFClass annotation consistent with all experimental evidence.

# ===== ISS annotations for sumoylation =====
- term:
    id: GO:0016925
    label: protein sumoylation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. EGR2 participates in protein sumoylation
      as an E3 SUMO ligase for NAB1/NAB2.
    action: ACCEPT
    reason: >-
      Correct. Experimentally validated in PMID:21836637. The ISS annotation from mouse
      is consistent with human experimental evidence.
    supported_by:
      - reference_id: PMID:21836637
        supporting_text: >-
          Krox20 functions as a SUMO ligase for its coregulators--the Nab proteins
- term:
    id: GO:0061665
    label: SUMO ligase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. EGR2 has E3 SUMO ligase activity,
      transferring SUMO1 to NAB coregulators via UBC9.
    action: ACCEPT
    reason: >-
      Core enzymatic function. Experimentally demonstrated in PMID:21836637 using human Krox20.
      UniProt lists this as a confirmed activity with EC number.
    supported_by:
      - reference_id: PMID:21836637
        supporting_text: >-
          we show that Krox20 functions as a SUMO ligase for its coregulators--the Nab
          proteins--and that Nab sumoylation negatively modulates Krox20 transcriptional
          activity in vivo

# ===== IDA annotations from PMID:12687019 =====
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:12687019
  review:
    summary: >-
      IDA annotation from Unoki and Nakamura 2003, which showed EGR2 directly binds
      promoter regions of BNIP3L and BAK to transactivate their expression.
    action: ACCEPT
    reason: >-
      Core function. Direct assay evidence showing EGR2 binds cis-regulatory regions of
      target genes and activates transcription.
    supported_by:
      - reference_id: PMID:12687019
        supporting_text: >-
          EGR2 directly transactivates expression of BNIP3L and BAK
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:12687019
  review:
    summary: >-
      IDA annotation for transcription activator activity from the study showing EGR2
      directly transactivates BNIP3L and BAK expression.
    action: ACCEPT
    reason: >-
      Core molecular function. This is a more specific child of GO:0000981 and accurately
      captures EGR2's role as a transcriptional activator. Consistent with the GO annotation
      guidelines for DNA-binding transcription factors.
    supported_by:
      - reference_id: PMID:12687019
        supporting_text: >-
          EGR2 could induce apoptosis in a large proportion of these lines ... EGR2 directly
          transactivates expression of BNIP3L and BAK
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:12687019
  review:
    summary: >-
      IDA annotation from the same study showing EGR2 positively regulates pol II
      transcription of BNIP3L and BAK.
    action: ACCEPT
    reason: >-
      Core function. Direct experimental evidence for transcriptional activation.

# ===== TAS annotations from Reactome =====
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9612073
  review:
    summary: >-
      TAS annotation from Reactome pathway for NGF- and MAPK-dependent EGR1, EGR2 and EGR4
      expression. Places EGR2 in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Correct localization. EGR2 functions in the nucleoplasm as a transcription factor.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9612483
  review:
    summary: >-
      TAS annotation from Reactome for EGR1,2,3 binding the NAB2 promoter. EGR2 binds
      the NAB2 promoter in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Correct. EGR2 regulates NAB2 expression as part of a negative feedback loop.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9613210
  review:
    summary: >-
      TAS annotation from Reactome for EGR1, EGR2 binding the RRAD promoter.
    action: ACCEPT
    reason: >-
      Correct localization for nucleoplasmic transcription factor activity.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9613213
  review:
    summary: >-
      TAS annotation from Reactome for NAB2 and CHD4 binding and repressing EGR-mediated
      RRAD gene expression.
    action: ACCEPT
    reason: >-
      Correct. EGR2-mediated transcription occurs in the nucleoplasm, and NAB2/CHD4 repress
      this activity.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9613476
  review:
    summary: >-
      TAS annotation from Reactome for EGR2:NAB2 and CHD4 binding the ID2 and ID4 promoter
      regions.
    action: ACCEPT
    reason: >-
      Correct localization for EGR2 transcriptional activity.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9613760
  review:
    summary: >-
      TAS annotation from Reactome for EGR2 gene expression.
    action: ACCEPT
    reason: >-
      Correct. EGR2 protein functions in the nucleoplasm.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9616116
  review:
    summary: >-
      TAS annotation from Reactome for EGR2 and SOX10 binding the MAG gene. This represents
      a well-characterized myelin gene target.
    action: ACCEPT
    reason: >-
      Correct. EGR2 cooperates with SOX10 to activate myelin gene expression in the
      nucleoplasm.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9618559
  review:
    summary: >-
      TAS annotation from Reactome for EGR2, SOX10 and TEAD1 binding enhancers in the PMP22
      gene.
    action: ACCEPT
    reason: >-
      Correct. PMP22 is a key myelin gene regulated by EGR2.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9618725
  review:
    summary: >-
      TAS annotation from Reactome for SOX10, EGR2 and NAB proteins binding the GJB1 promoter.
    action: ACCEPT
    reason: >-
      Correct. GJB1 (connexin 32) is another myelin gene target of EGR2.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9621400
  review:
    summary: >-
      TAS annotation from Reactome for EGR2 and SREBF2 dimer binding SCD5 gene.
    action: ACCEPT
    reason: >-
      Correct. EGR2 cooperates with SREBF2 to regulate lipid biosynthesis genes important
      for myelin formation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9621406
  review:
    summary: >-
      TAS annotation from Reactome for EGR2 and SREBF2 dimer binding CYP51A1 gene.
    action: ACCEPT
    reason: >-
      Correct. Another lipid biosynthesis gene regulated by EGR2 for myelin formation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9621411
  review:
    summary: >-
      TAS annotation from Reactome for EGR2 and SREBF2(1-484) dimer binding HMGCR gene.
    action: ACCEPT
    reason: >-
      Correct. HMGCR encodes a cholesterol biosynthesis enzyme important for myelin lipid
      composition.

# ===== Additional ISS annotations =====
- term:
    id: GO:0000976
    label: transcription cis-regulatory region binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. EGR2 binds cis-regulatory regions in
      promoters and enhancers of target genes.
    action: ACCEPT
    reason: >-
      Correct. Parent term of more specific DNA binding annotations.
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse Egr2. EGR2 binds chromatin at regulatory elements.
    action: ACCEPT
    reason: >-
      Correct. EGR2 binds chromatin in the context of regulating target gene expression.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for nuclear localization transferred from mouse Egr2.
    action: ACCEPT
    reason: >-
      Correct. Consistent with all other evidence.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for cytoplasmic localization from mouse Egr2.
    action: KEEP_AS_NON_CORE
    reason: >-
      EGR2 is primarily nuclear. Cytoplasmic localization is likely transient.
- term:
    id: GO:0006611
    label: protein export from nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for nuclear export from mouse Egr2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not core. Regulatory mechanism rather than primary function.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for positive regulation of transcription from mouse Egr2.
    action: ACCEPT
    reason: >-
      Core function. EGR2 is primarily a transcriptional activator.

# ===== IC annotation =====
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IC
  original_reference_id: PMID:14532282
  review:
    summary: >-
      IC (inferred by curator) annotation for nuclear localization, inferred from
      DNA-binding transcription factor activity (GO:0003700) demonstrated in PMID:14532282
      (HCF-1 as coactivator for Krox20).
    action: ACCEPT
    reason: >-
      Correct inference. A DNA-binding transcription factor must be in the nucleus to function.
    supported_by:
      - reference_id: PMID:14532282
        supporting_text: >-
          Krox20, a zinc finger transcription factor required for Schwann cell differentiation,
          ... showed a strong requirement for functional HCF-1 to activate transcription

# ===== Additional ISS annotations =====
- term:
    id: GO:0045444
    label: fat cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for fat cell differentiation from mouse Egr2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Peripheral function. Not a primary role for human EGR2.
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for TF binding from mouse Egr2. EGR2 interacts with other TFs and
      coregulators including SOX10, HCFC1, NAB1/NAB2.
    action: ACCEPT
    reason: >-
      Correct. EGR2 interacts with multiple TF-related proteins. HCFC1 interaction validated
      experimentally (PMID:14532282).

# ===== IPI annotation =====
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:19651900
  review:
    summary: >-
      IPI annotation showing EGR2 binds the E3 ubiquitin ligase WWP2 (AIP2, UniProtKB:O00308).
      WWP2 ubiquitinates EGR2, leading to its proteasomal degradation, which regulates
      activation-induced T cell death.
    action: ACCEPT
    reason: >-
      Experimentally validated interaction. EGR2 is a substrate of the ubiquitin ligase WWP2,
      and this interaction regulates EGR2 stability and consequently FasL expression in T cells.
    supported_by:
      - reference_id: PMID:19651900
        supporting_text: >-
          AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc
          finger transcription factor that has been found to regulate Fas ligand (FasL)
          expression during activation-induced T-cell death
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14532282
  review:
    summary: >-
      IPI annotation for protein binding with HCFC1 (UniProtKB:P51610). EGR2 contains an
      HCF-binding motif (DHLY at residues 162-165) that mediates interaction with HCFC1,
      which functions as a coactivator for EGR2.
    action: MODIFY
    reason: >-
      The term "protein binding" (GO:0005515) is too vague and uninformative. The interaction
      with HCFC1 is functionally significant as a transcriptional coactivation interaction.
      A more specific term should be used. The RNA polymerase II-specific DNA-binding
      transcription factor binding (GO:0061629) already captures this type of interaction.
    proposed_replacement_terms:
      - id: GO:0061629
        label: RNA polymerase II-specific DNA-binding transcription factor binding
    supported_by:
      - reference_id: PMID:14532282
        supporting_text: >-
          HCF-1 functions as a coactivator for the zinc finger protein Krox20 ... In Krox20,
          the HCF-binding motif lies within the N-terminal activation domain and mutation of
          this sequence diminishes both transactivation and association with the HCF-1
          beta-propeller

# ===== Additional IDA annotations =====
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IDA
  original_reference_id: PMID:14532282
  review:
    summary: >-
      IDA annotation from Luciano and Wilson 2003. The study demonstrated EGR2/Krox20 has
      transcription factor activity using reporter assays and showed that HCFC1 functions
      as its coactivator.
    action: ACCEPT
    reason: >-
      Core function. Direct assay evidence. While this is a parent of the more specific
      GO:0000981, it is acceptable as a separate IDA annotation.
    supported_by:
      - reference_id: PMID:14532282
        supporting_text: >-
          Krox20, a zinc finger transcription factor required for Schwann cell differentiation,
          ... showed a strong requirement for functional HCF-1 to activate transcription

# ===== TAS annotations from literature =====
- term:
    id: GO:0007420
    label: brain development
  evidence_type: TAS
  original_reference_id: PMID:9537424
  review:
    summary: >-
      TAS annotation for brain development from Warner et al. 1998. EGR2 is involved in
      hindbrain development through its role in rhombomere specification. Egr2 knockout mice
      show disrupted hindbrain segmentation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad developmental term. EGR2 is specifically involved in hindbrain segmentation
      rather than general brain development. The more specific rhombomere terms capture this
      role better. Keeping as non-core.
    supported_by:
      - reference_id: PMID:9537424
        supporting_text: >-
          Egr2(-/-) mice display disrupted hindbrain segmentation and development
- term:
    id: GO:0007422
    label: peripheral nervous system development
  evidence_type: TAS
  original_reference_id: PMID:9537424
  review:
    summary: >-
      TAS annotation for PNS development from Warner et al. 1998. EGR2 is critical for
      peripheral nerve myelination. The paper identified EGR2 mutations in patients with
      hereditary myelinopathies.
    action: ACCEPT
    reason: >-
      Core biological process. EGR2 is essential for PNS development through its role in
      Schwann cell myelination. Mutations cause inherited peripheral neuropathies.
    supported_by:
      - reference_id: PMID:9537424
        supporting_text: >-
          Stable expression of Egr2 is specifically associated with the onset of myelination
          in the peripheral nervous system ... we have identified one recessive and two
          dominant missense mutations in EGR2 ... in patients with congenital hypomyelinating
          neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)

references:
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000113
  title: Gene Ontology annotation of human sequence-specific DNA binding transcription
    factors (DbTFs) based on the TFClass database
  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:12687019
  title: EGR2 induces apoptosis in various cancer cell lines by direct transactivation
    of BNIP3L and BAK.
  findings:
    - statement: >-
        EGR2 directly transactivates expression of BNIP3L and BAK through binding to their
        promoter regions, inducing apoptosis in cancer cell lines.
      supporting_text: >-
        EGR2 could induce apoptosis in a large proportion of these lines by altering the
        permeability of mitochondrial membranes, releasing cytochrome c and activating
        caspase-3, -8, and -9. Analysis by cDNA microarray and subsequent functional
        studies revealed that EGR2 directly transactivates expression of BNIP3L and BAK.
- id: PMID:14532282
  title: HCF-1 functions as a coactivator for the zinc finger protein Krox20.
  findings:
    - statement: >-
        HCFC1 functions as a coactivator for EGR2/Krox20. The HCF-binding motif (DHLY at
        residues 162-165) in EGR2 mediates interaction with the HCFC1 beta-propeller domain.
        Mutation of this motif diminishes both transactivation and HCFC1 association.
      supporting_text: >-
        Krox20, a zinc finger transcription factor required for Schwann cell differentiation,
        and E2F4, a cell cycle regulator, showed a strong requirement for functional HCF-1
        to activate transcription ... In Krox20, the HCF-binding motif lies within the
        N-terminal activation domain and mutation of this sequence diminishes both
        transactivation and association with the HCF-1 beta-propeller
- id: PMID:17717711
  title: Functional, histopathologic and natural history study of neuropathy associated
    with EGR2 mutations.
  findings:
    - statement: >-
        Characterization of EGR2 mutations causing CMT1D/CHN/DSS. R359W and E412K mutations
        cause loss of DNA binding and transactivation. I268N affects the NAB repressor binding
        site. Cranial nerve dysfunction and respiratory compromise are common features.
      supporting_text: >-
        Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and
        related inherited peripheral neuropathies ... respiratory compromise and cranial
        nerve dysfunction are commonly associated with EGR2 mutations
- id: PMID:19651900
  title: The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell
    death by catalyzing EGR2 ubiquitination.
  findings:
    - statement: >-
        WWP2/AIP2 interacts with and ubiquitinates EGR2, promoting its proteasomal degradation.
        EGR2 regulates FasL expression in T cells during activation-induced cell death. AIP2-mediated
        EGR2 degradation protects against T cell apoptosis.
      supporting_text: >-
        AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc
        finger transcription factor that has been found to regulate Fas ligand (FasL)
        expression during activation-induced T-cell death
- id: PMID:21836637
  title: The transcription factor Krox20 is an E3 ligase that sumoylates its Nab coregulators.
  findings:
    - statement: >-
        EGR2/Krox20 functions as an E3 SUMO ligase, catalyzing SUMO1 conjugation to its NAB
        coregulators. This requires interaction with the SUMO-conjugating enzyme UBC9. NAB
        sumoylation negatively modulates EGR2 transcriptional activity.
      supporting_text: >-
        we show that Krox20 functions as a SUMO ligase for its coregulators--the Nab
        proteins--and that Nab sumoylation negatively modulates Krox20 transcriptional
        activity in vivo
- id: PMID:28473536
  title: Impact of cytosine methylation on DNA binding specificities of human transcription
    factors.
  findings:
    - statement: >-
        Systematic SELEX analysis of 542 human TFs including EGR2 characterized binding
        specificities on both unmethylated and CpG-methylated DNA.
      supporting_text: >-
        By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution
        of ligands by exponential enrichment), we found that there are also many TFs
        that prefer CpG-methylated sequences
- id: PMID:9537424
  title: Mutations in the early growth response 2 (EGR2) gene are associated with
    hereditary myelinopathies.
  findings:
    - statement: >-
        First identification of EGR2 mutations causing human myelinopathies. Recessive and
        dominant missense mutations found in patients with CHN and CMT1. Egr2 knockout mice
        show disrupted hindbrain development and a block in Schwann cell differentiation.
      supporting_text: >-
        Stable expression of Egr2 is specifically associated with the onset of myelination
        in the peripheral nervous system (PNS). Egr2(-/-) mice display disrupted hindbrain
        segmentation and development, and a block of Schwann-cell differentiation at an
        early stage
- id: Reactome:R-HSA-9612073
  title: NGF- and MAPK-dependent EGR1, EGR2 and EGR4 expression
  findings: []
- id: Reactome:R-HSA-9612483
  title: EGR1,2,3 bind the NAB2 promoter
  findings: []
- id: Reactome:R-HSA-9613210
  title: EGR1, EGR2 bind the RRAD promoter
  findings: []
- id: Reactome:R-HSA-9613213
  title: NAB2 and CHD4 bind and repress EGR-mediated RRAD gene expression
  findings: []
- id: Reactome:R-HSA-9613476
  title: EGR2:NAB2 and CHD4 bind the ID2 and ID4 promoter regions
  findings: []
- id: Reactome:R-HSA-9613760
  title: EGR2 gene expression
  findings: []
- id: Reactome:R-HSA-9616116
  title: EGR2 and SOX10 bind the MAG gene
  findings: []
- id: Reactome:R-HSA-9618559
  title: EGR2, SOX10 and TEAD1 bind enhancers in the PMP22 gene
  findings: []
- id: Reactome:R-HSA-9618725
  title: SOX10, EGR2 and NAB proteins bind the GJB1 promoter
  findings: []
- id: Reactome:R-HSA-9621400
  title: EGR2 and SREBF2 dimer bind SCD5 gene
  findings: []
- id: Reactome:R-HSA-9621406
  title: EGR2 and SREBF2 dimer bind CYP51A1 gene
  findings: []
- id: Reactome:R-HSA-9621411
  title: EGR2 and SREBF2(1-484) dimer bind HMGCR gene
  findings: []
- id: file:human/EGR2/EGR2-deep-research-falcon.md
  title: Deep research report on EGR2 function (Falcon provider)
  findings:
    - statement: >-
        EGR2 is a nuclear C2H2 zinc-finger transcription factor that binds GC-rich EGR
        motifs and recruits NAB1/2 to activate or repress target genes, serving as a master
        regulator of myelin programs in Schwann cells and a node in immune tolerance and
        dysfunction circuits.

core_functions:
- description: >-
    DNA-binding transcription activator activity: EGR2 enables DNA-binding transcription
    activator activity, RNA polymerase II-specific (GO:0001228). It binds GC-rich EGR consensus
    sequences (5'-GCGGGGGCG-3') through three C2H2 zinc finger domains and activates transcription
    of target genes in the nucleus. Key direct targets include myelin structural genes (MPZ,
    PMP22, GJB1, MAG), HOX genes (HOXB2, HOXB3, HOXA4), NAB2, BNIP3L, and BAK.
  molecular_function:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  directly_involved_in:
    - id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  locations:
    - id: GO:0005634
      label: nucleus
  supported_by:
    - reference_id: PMID:17717711
      supporting_text: >-
        Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and
        related inherited peripheral neuropathies
    - reference_id: PMID:12687019
      supporting_text: >-
        EGR2 directly transactivates expression of BNIP3L and BAK
    - reference_id: PMID:14532282
      supporting_text: >-
        Krox20, a zinc finger transcription factor required for Schwann cell differentiation,
        and E2F4, a cell cycle regulator, showed a strong requirement for functional HCF-1
        to activate transcription

- description: >-
    E3 SUMO ligase activity: EGR2 enables SUMO ligase activity (GO:0061665), catalyzing
    transfer of SUMO1 to its NAB1 and NAB2 coregulators in collaboration with the SUMO-conjugating
    enzyme UBC9. NAB sumoylation negatively modulates EGR2 transcriptional activity, providing
    a negative feedback mechanism.
  molecular_function:
    id: GO:0061665
    label: SUMO ligase activity
  directly_involved_in:
    - id: GO:0016925
      label: protein sumoylation
  locations:
    - id: GO:0005634
      label: nucleus
  supported_by:
    - reference_id: PMID:21836637
      supporting_text: >-
        we show that Krox20 functions as a SUMO ligase for its coregulators--the Nab
        proteins--and that Nab sumoylation negatively modulates Krox20 transcriptional
        activity in vivo

- description: >-
    Positive regulation of Schwann cell myelination: EGR2 is a master regulator of peripheral
    nervous system myelination. It promotes Schwann cell differentiation from the premyelinating
    to the myelinating state, activating myelin structural genes (MPZ, PMP22, GJB1, MAG)
    cooperatively with SOX10 and lipid biosynthesis genes (SCD5, CYP51A1, HMGCR) with SREBF2.
    Loss-of-function mutations cause Charcot-Marie-Tooth disease type 1D, Dejerine-Sottas
    syndrome, and congenital hypomyelinating neuropathy.
  molecular_function:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  directly_involved_in:
    - id: GO:0031643
      label: positive regulation of myelination
    - id: GO:0014040
      label: positive regulation of Schwann cell differentiation
  supported_by:
    - reference_id: PMID:9537424
      supporting_text: >-
        Stable expression of Egr2 is specifically associated with the onset of myelination
        in the peripheral nervous system (PNS). Egr2(-/-) mice display disrupted hindbrain
        segmentation and development, and a block of Schwann-cell differentiation at an
        early stage
    - reference_id: PMID:17717711
      supporting_text: >-
        Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and
        related inherited peripheral neuropathies

- description: >-
    Hindbrain segmentation: EGR2 is specifically expressed in and required for proper
    specification of rhombomeres 3 and 5 during hindbrain development, controlling expression
    of HOX genes (HOXB2, HOXB3, HOXA4) that specify rhombomere identity. This is a conserved
    developmental function.
  molecular_function:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  directly_involved_in:
    - id: GO:0035284
      label: brain segmentation
  supported_by:
    - reference_id: PMID:9537424
      supporting_text: >-
        Egr2(-/-) mice display disrupted hindbrain segmentation and development