FOXE1 is a nuclear forkhead transcription factor that binds cis-regulatory DNA and controls gene expression in thyroid and craniofacial development. Its targets include the thyroid differentiation genes TG and TPO and the developmental regulators MSX1 and TGFB3. It acts with other transcription factors, including ELK1, in promoter-dependent gene regulation. FOXE1 is required for normal thyroid formation and palate development. Biallelic pathogenic variants cause Bamforth–Lazarus syndrome, characterized by thyroid dysgenesis and craniofacial malformations.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Chromatin association is consistent with the defined transcription-factor mechanism. Reason: The original TFClass classification is corroborated by tagged human FOXE1 ChIP at endogenous MSX1/TGFB3 promoter chromatin in 21177256. Retain chromatin as a supported functional location while distinguishing overexpressed tagged occupancy from endogenous untagged binding, a stable chromatin complex or continuous residence. TERT association from 27852061 is also not equated with direct FOXE1 motif contact. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: FOXE1 recognizes Pol II regulatory DNA through its forkhead domain. Reason: The authentic PTHR11829 tree places human O00358 beneath the positive PTN000930906 IBD node, with an exact 373-aa target MSA match. Human WT FOXE1 EMSA, competitor/supershift controls and promoter experiments in 9697705 and 21177256 independently support cis-regulatory sequence recognition. The phylogenetic assertion is consistent with the target biology; it is not a donor-count inference or a claim that every ancestral source was newly assayed. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved Pol II DNA-binding transcription-factor activity is defining for FOXE1. Reason: The positive PTN000930906 IBD is on the verified human target path. Human FOXE1 DNA binding and transcriptional reporter responses in 12165566, 21177256 and 24219130 establish the core activity. O00358 appearing among descendant evidence is legitimate target experimental support. Current versus retained historical donor-list differences do not alter the verified node descent or justify rewriting the original source groups. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:24219130 A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome c... | ACCEPT | Summary: WT and R73S human FOXE1 have measurable transcription-factor activity. Reason: Selected original 24219130 Methods and Results show human WT and R73S FOXE1 acting on human TG/TPO reporters in HEK293 cells, with matched protein abundance and no detected EMSA binding difference. The R73S reporter increase supports altered activity rather than universal loss across disease-associated variants. Primary-thyrocyte TG protein abundance is a distinct endpoint with higher mutant FOXE1 abundance; it is not a direct endogenous transcription-rate measurement. Supporting Evidence: |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: The rat-derived TF inference agrees with direct human FOXE1 assays. Reason: The captured A6IJB5 donor has an experimental TF annotation from 9214635. That paper assays rat TTF2, including DNA binding and promoter-specific repression in a human HeLa host. Separate human FOXE1 binding/reporter studies establish conservation of the general Pol II TF activity. The original IEA and alternative Ensembl identifier remain intact; the rat insert is not relabeled as human and the Ensembl source annotation is not claimed independently reconstructed. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:12165566 A novel loss-of-function mutation in TTF-2 is associated wit... | ACCEPT | Summary: Human S57N comparison supports WT FOXE1 transcription-factor activity. Reason: In 12165566, sequence-checked human WT and S57N constructs were compared by TG-site binding and a synthetic reporter containing rat TPO sites. WT activates the reporter, while S57N retains reduced binding and partial activation. This supports human FOXE1 TF activity; neither complete S57N loss nor endogenous human promoter occupancy follows from this reporter. Supporting Evidence: |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:16882747 A novel missense mutation in human TTF-2 (FKHL15) gene assoc... | ACCEPT | Summary: Human R102C comparison supports WT promoter activation coupled to DNA recognition. Reason: The selected 16882747 Methods and Results compare human WT and R102C FOXE1 using TG-probe EMSA and a human TPO promoter reporter in 293-EBNA cells with TTF1 coexpression. WT binds and activates, whereas R102C has negligible activity in those assays. The core TF assertion is supported without treating the historical 367-aa description as a reconstructed current natural product. Supporting Evidence: |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:20094846 Characterization of mutations in the FOXE1 gene in a cohort ... | ACCEPT | Summary: The N132D study measures FOXE1 TF activity without establishing variant causality. Reason: The 20094846 study uses human WT and N132D inserts in HepG2 cells, a TG-probe binding assay and a separate human TPO promoter reporter. These experiments support TF capacity. The reported quantitative binding descriptions conflict, and the authors conclude N132D is not the cause of thyroid dysgenesis in the patient; neither issue erases the WT activity or makes the variant a proven disease allele. Supporting Evidence: |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:20484477 Maternal isodisomy for chromosome 9 causing homozygosity for... | ACCEPT | Summary: FOXE1 Pol II transcription-factor activity is established independently of the uninspected F137S assay. Reason: Human FOXE1 DNA binding and promoter-dependent transcription in independently inspected 12165566, 21177256 and 24219130 establish the unrestricted Pol II DNA-binding transcription-factor capacity. The authentic 20484477 abstract reports failed DNA binding and negligible transfection activity for F137S and is consistent with that capacity. Accept the gene-level claim and retain its original IMP provenance, while explicitly leaving the F137S constructs, promoter substrates and controls unverified. Corroboration does not certify the unseen experiment. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:21177256 MSX1 and TGF-beta3 are novel target genes functionally regul... | ACCEPT | Summary: Human FOXE1 regulates MSX1 and TGFB3 promoter activity. Reason: In 21177256, sequence-checked human FOXE1 constructs in 293-EBNA cells regulate MSX1/TGFB3 expression and promoter reporters. Nuclear-extract binding controls and tagged ChIP provide complementary evidence. Mouse palate transcript effects are a separate developmental result. These human assays establish the TF activity without claiming purified affinity, endogenous untagged occupancy or a native human palate perturbation. Supporting Evidence: |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: The forkhead TF classification matches the experimentally demonstrated activity. Reason: TFClass 3.3.1 is the original classification source. Sequence-specific binding together with target-promoter regulation by human FOXE1 in 9697705 and 21177256 supports the Pol II DNA-binding TF term beyond the classification alone. This retains the imported ISA provenance without presenting it as an additional experimental assay. |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | TOO GENERAL | Summary: Generic DNA binding adds no specificity beyond the retained regulatory sequence-binding activity. Reason: The rat donor and human EMSA studies support real DNA binding, but GO:0000978 is an official descendant of GO:0003677 and specifies the relevant regulatory recognition. Retain the original rat/Ensembl IEA source context while treating this generic term as redundant functional coverage, not as a false interaction with DNA. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:9697705 Mutation of the gene encoding human TTF-2 associated with th... | TOO GENERAL | Summary: The original WT/A65V experiment supports the retained, more specific Pol II TF activity. Reason: In 9697705, human WT FOXE1 binds a TG probe and activates a synthetic reporter, whereas A65V has negligible activity with comparable nuclear protein abundance. The experimentally supported TF mechanism is represented by the more specific GO:0000981 already retained. This classification does not question the original IDA experiment or erase its source-specific evidence. Supporting Evidence: |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: The domain-based TF assignment is represented more precisely by Pol II-specific TF activity. Reason: The three original InterPro sources agree with FOXE1 being a forkhead transcription factor. GO:0000981 is an official descendant of GO:0003700 and captures the supported human promoter-regulatory activity. The electronic domain assertion is sound but supplies no distinct activity beyond that retained term. |
| GO:0005515 protein binding | IPI PMID:27852061 Thyroid transcription factor FOXE1 interacts with ETS factor... | MODIFY | Summary: FOXE1 associates with the DNA-binding transcription factor ELK1 in human thyroid and cellular interaction assays. Reason: The original study supports FOXE1 association with ELK1, an established RNA polymerase II-specific DNA-binding transcription factor. Tagged proteins co-immunoprecipitated in human NThy thyroid cells, endogenous proteins co-immunoprecipitated from human Graves thyroid tissue, and a mammalian two-hybrid assay tested FOXE1 residues 164–373 with full-length ELK1. These source-specific results justify the more informative transcription-factor-binding class. Co-IP and cellular two-hybrid evidence do not establish purified binary affinity or a unique interface; the authors explicitly allow endogenous ELK1-mediated bridging for some truncation results. The refinement preserves the original human interaction context and does not assign every assay to full-length FOXE1 or assert direct FOXE1 contact with the TERT DNA sequence. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear activity is supported by the verified phylogeny and human experiments. Reason: The positive nucleus IBD at PTN000930906 lies on the authentic human O00358 path, with the exact target sequence reproduced by the MSA. Human FOXE1 recovery in nuclear extracts and tagged promoter ChIP support nuclear access and function. Self-donor evidence is legitimate. Neither the IBA nor these assays establishes exclusive nuclear localization in every cell state. |
| GO:0005634 nucleus | IDA PMID:21177256 MSX1 and TGF-beta3 are novel target genes functionally regul... | ACCEPT | Summary: The human tagged FOXE1 experiments establish nuclear access. Reason: In 21177256, human FOXE1 is recovered in nuclear extracts used for controlled EMSA and is assayed by anti-V5 ChIP at endogenous promoters. These support the original nucleus annotation in the transfected cell context. No exclusive localization, endogenous untagged microscopy or natural-product-specific targeting difference is inferred. Supporting Evidence: |
| GO:0005634 nucleus | IDA PMID:9697705 Mutation of the gene encoding human TTF-2 associated with th... | ACCEPT | Summary: Human WT and A65V FOXE1 are detected in the tested nuclear fraction. Reason: The 9697705 binding experiments use transfected 293 nuclear extracts with anti-FLAG supershift and comparable WT/A65V nuclear protein abundance. Nuclear access is therefore directly supported independently of whether the mutant binds DNA efficiently. This does not establish exclusive or native tissue localization. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt nuclear-location inference agrees with measured human nuclear access. Reason: The original SL-0191 electronic location is consistent with human FOXE1 nuclear extracts and promoter-associated tagged ChIP in the inspected studies. This is a defining cellular location for its transcriptional activity. It does not imply that FOXE1 is absent from all other compartments or that each construct was examined by endogenous localization microscopy. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | TOO GENERAL | Summary: Broad transcription regulation is represented by the retained Pol II-specific process. Reason: The InterPro inference is compatible with FOXE1 biology, but GO:0006357 is an official descendant of GO:0006355 and describes the established target-promoter responses. Positive human activation and rat promoter-specific repression fit the broader Pol II regulatory process without requiring a second generic transcription process. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved Pol II transcriptional regulation is supported by both phylogeny and human experiments. Reason: The exact target path contains the positive PTN000930906 IBD for this process, and the aligned human sequence matches the official 373-aa protein. Human binding, promoter-reporter and target-expression assays support active regulation rather than merely a downstream phenotype. Target O00358 among descendant sources is valid experimental grounding; the current/historical source-list difference remains preserved. |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:24219130 A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome c... | ACCEPT | Summary: Human WT and R73S reporter responses establish Pol II transcriptional regulation. Reason: The 24219130 HEK293 assays use human TG/TPO promoters and matched FOXE1 abundance, with R73S showing increased reporter output. The source’s abstract and Results swap precise promoter fold labels, so no such attribution is made here. In primary thyrocytes the measured TG endpoint is Western-blot protein abundance and mutant FOXE1 abundance is higher; that result is not presented as a directly measured endogenous transcription rate. Supporting Evidence: |
| GO:0006357 regulation of transcription by RNA polymerase II | IMP PMID:12165566 A novel loss-of-function mutation in TTF-2 is associated wit... | ACCEPT | Summary: Human WT FOXE1 regulates a defined promoter reporter, with partial S57N impairment. Reason: The sequence-checked human constructs in 12165566 are compared on a synthetic rat-TPO-site/TK reporter. WT activates and S57N retains reduced activation. This measures transcriptional regulation in the transfection system; the patients’ anatomical phenotypes and the binding assay are separate endpoints, and endogenous human promoter regulation is not claimed from the reporter alone. Supporting Evidence: |
| GO:0006357 regulation of transcription by RNA polymerase II | IMP PMID:16882747 A novel missense mutation in human TTF-2 (FKHL15) gene assoc... | ACCEPT | Summary: Human FOXE1 regulates the tested human TPO promoter in a defined cofactor context. Reason: The selected 16882747 Methods/Results describe a human TPO −366/+50 reporter in 293-EBNA cells with TTF1 coexpression. WT activation and R102C impairment establish regulatory capacity under those conditions. The cofactor context, human insert and cell host remain explicit; no all-promoter or all-variant conclusion follows. Supporting Evidence: |
| GO:0006357 regulation of transcription by RNA polymerase II | IMP PMID:20094846 Characterization of mutations in the FOXE1 gene in a cohort ... | ACCEPT | Summary: The N132D study supports human TPO reporter regulation without proving disease causation. Reason: The 20094846 human TPO reporter is distinct from the TG-probe EMSA. Human WT and N132D FOXE1 affect reporter output in HepG2 cells. This supports the regulatory process, while the authors’ conclusion that N132D is not the cause of the patient’s dysgenesis and the inconsistent binding-effect numbers remain explicit limits. Supporting Evidence: |
| GO:0006357 regulation of transcription by RNA polymerase II | IMP PMID:20484477 Maternal isodisomy for chromosome 9 causing homozygosity for... | ACCEPT | Summary: FOXE1-mediated Pol II regulation is established, with the original F137S assay access limit retained. Reason: Independently inspected human FOXE1 reporter and target-gene experiments in 12165566, 21177256 and 24219130 establish regulation of transcription by RNA polymerase II. The authentic 20484477 abstract reports negligible F137S transfection activity, consistent with that gene-level capacity. Accept this unrestricted functional claim without claiming that the original reporter design, protein normalization or controls were inspected. The original IMP row and citation remain intact; the F137S paper retains its UNVERIFIED reference assessment. |
| GO:0006357 regulation of transcription by RNA polymerase II | IMP PMID:21177256 MSX1 and TGF-beta3 are novel target genes functionally regul... | ACCEPT | Summary: Human FOXE1 controls MSX1/TGFB3 expression and promoter reporters. Reason: In 21177256, human FOXE1 transfection alters MSX1/TGFB3 RNA/protein and promoter reporters, with binding and tagged occupancy providing mechanistic context. The transcription factor itself regulates the gene-expression step. Reduced Msx1/Tgfb3 transcripts in mouse palate/dental compartments are separate corroboration, not a native human developmental rescue. Supporting Evidence: |
| GO:0006590 thyroid hormone generation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Thyroid developmental and transcriptional roles do not establish participation in hormone-generating chemistry. Reason: The exact current mouse donor uses the broader acts_upstream_of_or_within relation and points to 9697704: Foxe1-null thyroid abnormalities accompany reduced neonatal FT4 and increased TSH. GO:0006590 specifically describes thyroid-hormone formation through iodination, coupling and precursor processing. Those observations establish a developmental requirement for endocrine output; human FOXE1 regulation of TG/TPO expression is upstream regulation, not evidence that FOXE1 performs or supplies a structural/cofactor step of hormone generation. The transferred activity scope is therefore excessive, while its original ISS/Q8R2I0 provenance and positive endocrine phenotype are retained. |
| GO:0009653 anatomical structure morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: FOXE1 participates in morphogenetic gene programs within the verified inherited clade. Reason: The actual PTHR11829 target path supports the positive PTN000930906 IBD, and human pathogenic variants plus mouse thyroid/palatal genetics substantiate morphogenetic involvement. The broad developmental process is retained contextually rather than promoted to a separate molecular core. There is no target-path error, donor-count objection or asserted loss of inherited function. |
| GO:0009653 anatomical structure morphogenesis | NAS PMID:9169137 FKHL15, a new human member of the forkhead gene family locat... | KEEP AS NON CORE | Summary: FOXE1 morphogenetic involvement is supported independently of the original cloning-paper citation. Reason: Human pathogenic variants in 12165566 and 9697705, together with mouse Foxe1 developmental genetics in 9697704, independently establish a role in thyroid and palatal morphogenesis. Retain the unrestricted developmental claim as non-core without treating the family discussion in the authentic 9169137 abstract as a target perturbation. That cloning paper’s original body and the precise basis of this NAS citation remain unverified; its reference assessment and original provenance are unchanged. |
| GO:0016477 cell migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Foxe1-dependent thyroid-primordium migration is retained with the actual rescue species. Reason: The exact mouse donor in 15581879 links Foxe1 loss to failed bud migration and tests spatially restricted rescue. The construct inserts rat Foxe1 cDNA into the mouse Titf1 locus; migration is restored when expression is confined to the primordium. This supports a transcriptionally controlled migration program, not direct motility by FOXE1 or a human rescue. Pax8-null buds can migrate despite undetectable Foxe1, so the role is context dependent. The original mouse donor uses acts_upstream_of_or_within, a broader claim than the preserved human involved_in transfer; the contextual judgment rests on the actual perturbation/rescue evidence, not relabeling that donor as a direct assay. Supporting Evidence: |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited differentiation role is compatible with FOXE1-controlled tissue gene programs. Reason: Human FOXE1 target-promoter regulation and mouse thyroid/palatal developmental evidence support a role in establishing differentiated gene-expression states. The positive PTN000930906 IBD lies on the verified human path. This broad process is retained as developmental context without claiming every cell lineage requires FOXE1 or converting phenotype into an independent catalytic function. |
| GO:0030878 thyroid gland development | IEP PMID:15494458 PAX8, TITF1, and FOXE1 gene expression patterns during human... | KEEP AS NON CORE | Summary: Human thyroid expression fits an independently supported thyroid-development role. Reason: The original 15494458 study detects human FOXE1 RNA in the developing thyroid from CS15 using controlled in-situ hybridization; this is expression evidence, not a perturbation. Independent human loss-of-function phenotypes and mouse thyroid development support the contextual association. Retain the exact IEP source while keeping its evidence distinct from the functional studies and from PAX8/TITF1 results in the same paper. |
| GO:0030878 thyroid gland development | IMP PMID:9697705 Mutation of the gene encoding human TTF-2 associated with th... | KEEP AS NON CORE | Summary: Human FOXE1 dysfunction is associated with severe thyroid developmental failure. Reason: The 9697705 study reports thyroid agenesis in affected human siblings and functionally impaired A65V FOXE1, with WT binding/reporter controls. This supports thyroid-development participation through the gene-regulatory program. It does not establish a precise cellular-autonomy mechanism, and other FOXE1 variants can retain a eutopic gland, so agenesis is not universal. |
| GO:0031069 hair follicle morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse skin-graft evidence supports a contextual hair-follicle morphogenetic role. Reason: The exact mouse donor uses acts_upstream_of_or_within; source 15367491 compares Foxe1-null skin grafts in immunodeficient hosts. Early skin morphology is similar, but later follicles and hairs have altered orientation and form despite retained lineage markers. This supports local skin developmental involvement and limits systemic hypothyroidism as the sole explanation. It does not establish an isolated human follicle mechanism; human BCC expression and Gli2 regulation of the rat Foxe1 promoter are separate assays. Supporting Evidence: |
| GO:0032869 cellular response to insulin stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: Insulin-responsive FOXE1 expression does not settle the exact transferred cellular-response role. Reason: Selected original 9214635 Results show insulin-regulated rat TTF2 RNA in FRTL5 cells; 9287345 provides abstract-level corroboration. The captured current A6IJB5 annotations do not contain this exact GO term, and the alternate Ensembl provenance has not been independently reconstructed. The broad response definition includes gene-expression changes, but these observations do not resolve whether FOXE1 performs a downstream insulin-response program or is the regulated output. Preserve the IEA and both original source alternatives without declaring the historical inference false. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:24219130 A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome c... | TOO GENERAL | Summary: Sequence-specific DNA binding is supported and subsumed by retained Pol II cis-regulatory DNA binding. Reason: Selected 24219130 Methods/Results show EMSA with human TG/TPO promoter probes and no detected WT–R73S binding difference. This supports recognition capacity independently of the separate reporter-activation differences. The primary-thyrocyte protein-abundance result is not used as a DNA-binding assay. The original sequence-specific DNA-binding term is true but subsumed by the independently retained GO:0000978 Pol II cis-regulatory DNA-binding activity. TOO_GENERAL concerns that gene-level granularity and does not discount this source-specific experiment. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IDA PMID:9697705 Mutation of the gene encoding human TTF-2 associated with th... | TOO GENERAL | Summary: Sequence-specific DNA binding is supported and subsumed by retained Pol II cis-regulatory DNA binding. Reason: The 9697705 experiment uses a TG oligonucleotide, translated protein and transfected 293 nuclear extracts with anti-FLAG supershift and comparable WT/mutant nuclear abundance. WT recognition and A65V loss support the original sequence-specific binding assertion. The synthetic rat-TPO-site reporter addresses transcription separately. The original sequence-specific DNA-binding term is true but subsumed by the independently retained GO:0000978 Pol II cis-regulatory DNA-binding activity. TOO_GENERAL concerns that gene-level granularity and does not discount this source-specific experiment. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000002 | TOO GENERAL | Summary: The forkhead domain inference is consistent with the more specific retained DNA-binding activity. Reason: The InterPro forkhead assignments are consistent with sequence recognition. Retained GO:0000978 is a verified is_a descendant of GO:0043565 and is independently supported by human FOXE1 promoter-binding experiments. The unrestricted sequence-specific DNA-binding claim is therefore true but subsumed, as for the other original rows carrying this term. This granularity judgment does not convert the electronic domain inference into an experimental assertion. |
| GO:0043565 sequence-specific DNA binding | IMP PMID:12165566 A novel loss-of-function mutation in TTF-2 is associated wit... | TOO GENERAL | Summary: Sequence-specific DNA binding is supported and subsumed by retained Pol II cis-regulatory DNA binding. Reason: In 12165566, translated human FOXE1 and transfected 293-EBNA nuclear extracts form TG-probe complexes; equal protein and antibody-supershift controls support attribution to FOXE1. S57N retains diminished binding. This directly measured recognition capacity is integral to TF function, although it is not purified equilibrium binding or endogenous chromatin occupancy. The original sequence-specific DNA-binding term is true but subsumed by the independently retained GO:0000978 Pol II cis-regulatory DNA-binding activity. TOO_GENERAL concerns that gene-level granularity and does not discount this source-specific experiment. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IMP PMID:16882747 A novel missense mutation in human TTF-2 (FKHL15) gene assoc... | TOO GENERAL | Summary: Sequence-specific DNA binding is supported and subsumed by retained Pol II cis-regulatory DNA binding. Reason: The selected 16882747 Methods identify a TG oligonucleotide and equal in-vitro translation comparisons. WT binds while R102C has negligible binding. The sequence-specific DNA-binding assertion is supported within that extract-based assay; a reporter using human TPO is a separate regulatory experiment. The original sequence-specific DNA-binding term is true but subsumed by the independently retained GO:0000978 Pol II cis-regulatory DNA-binding activity. TOO_GENERAL concerns that gene-level granularity and does not discount this source-specific experiment. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IMP PMID:20094846 Characterization of mutations in the FOXE1 gene in a cohort ... | TOO GENERAL | Summary: Sequence-specific DNA binding is supported and subsumed by retained Pol II cis-regulatory DNA binding. Reason: The actual 20094846 Methods and Figure 3 identify a TG promoter probe with unlabeled competition in HepG2 nuclear extracts. Abstract/Results shorthand instead calls the binding target TPO, and Results/Discussion differ over effect size. The specified probe and competition support sequence-specific recognition, but no reconciled magnitude or causal N132D disease interpretation is asserted. The original sequence-specific DNA-binding term is true but subsumed by the independently retained GO:0000978 Pol II cis-regulatory DNA-binding activity. TOO_GENERAL concerns that gene-level granularity and does not discount this source-specific experiment. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IMP PMID:20484477 Maternal isodisomy for chromosome 9 causing homozygosity for... | TOO GENERAL | Summary: The general DNA-binding claim is subsumed; the original F137S experiment remains unverified. Reason: The authentic 20484477 abstract reports failed F137S DNA binding, but its original probe, construct and binding controls were not recovered. Independently inspected human FOXE1 promoter-binding experiments in 9697705 and 21177256 establish the more specific retained GO:0000978 activity, which entails GO:0043565. TOO_GENERAL therefore records the same gene-level granularity verdict as the other rows with this unrestricted term; it does not authenticate the unseen F137S assay or resolve its source-specific verification limit. |
| GO:0043565 sequence-specific DNA binding | IMP PMID:21177256 MSX1 and TGF-beta3 are novel target genes functionally regul... | TOO GENERAL | Summary: Sequence-specific DNA binding is supported and subsumed by retained Pol II cis-regulatory DNA binding. Reason: The 21177256 study uses human FOXE1 nuclear extracts, anti-V5 supershift, competitor and mutated-probe controls together with tagged ChIP on endogenous promoter chromatin. These complementary experiments support sequence recognition in the tested system. Tagged overexpression and nuclear extracts do not establish purified affinity or native human-palate occupancy. The original sequence-specific DNA-binding term is true but subsumed by the independently retained GO:0000978 Pol II cis-regulatory DNA-binding activity. TOO_GENERAL concerns that gene-level granularity and does not discount this source-specific experiment. Supporting Evidence: |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000107 | MODIFY | Summary: The rat donor supports promoter-specific negative regulation at Pol II promoters. Reason: The original 9214635 experiments assay rat TTF2 in human HeLa cells and show repression of TTF1-driven TG and PAX8-driven TPO reporters, with unaffected control promoters. These protein-coding promoters support the more specific GO:0000122 negative regulation of transcription by RNA polymerase II. Repression persists after alteration of cognate TTF2 sites, so a DNA-bound repressor mechanism is not implied. Preserve the original human IEA and both donor alternatives; the rat insert is not relabeled as directly tested human FOXE1, and this promoter-specific evidence does not establish universal repression. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9697705 Mutation of the gene encoding human TTF-2 associated with th... | MODIFY | Summary: Human FOXE1 activates the tested Pol II reporter, supporting a more specific positive-regulation term. Reason: In 9697705, human WT FOXE1 activates a synthetic reporter with repeated rat TPO regulatory sites linked to the thymidine kinase promoter, whereas A65V has negligible activity at comparable nuclear abundance. This Pol II reporter supports GO:0045944 positive regulation of transcription by RNA polymerase II rather than the broader DNA-templated term. The result remains promoter- and construct-specific; it does not negate the separate rat repression experiments or establish equivalent effects at every endogenous human target. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | TOO GENERAL | Summary: Broad organ development is already represented by supported thyroid and palatal contexts. Reason: The ARBA inference is compatible with known FOXE1 developmental roles, but thyroid gland development is an official descendant of animal organ development and is retained with human and mouse evidence. This broad electronic term adds no distinct organ or mechanism. Its original ARBA source is preserved rather than presented as newly inspected experimental evidence. |
| GO:0048538 thymus development | IEP PMID:15494458 PAX8, TITF1, and FOXE1 gene expression patterns during human... | UNDECIDED | Summary: Human thymic expression is real, but a developmental function is unresolved. Reason: The original 15494458 study detects human FOXE1 RNA in fetal thymus and explicitly leaves its functional significance unresolved. No FOXE1 perturbation or downstream thymic gene program was assayed. The mouse 9697704 report of normal-appearing thymus is limited and does not refute a human role. Retain the source-specific IEP context as undecided instead of treating expression as demonstrated developmental participation or dismissing it as a wrong citation. |
| GO:0048562 embryonic organ morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The mouse donor supports embryonic thyroid morphogenesis through a gene-regulatory role. Reason: The exact mouse IMP donor uses acts_upstream_of_or_within; source 9697704 shows a formed thyroid bud that fails normal descent or is lost in Foxe1-null embryos, with variable ectopic thyroid remnants. This supports embryonic organ morphogenesis as a developmental consequence of FOXE1 function. Preserve the human ISS transfer and do not infer an identical human cellular mechanism or hormone-synthetic catalytic activity. Supporting Evidence: |
| GO:0048731 system development | IEA GO_REF:0000117 | TOO GENERAL | Summary: System development is broader than the retained organ-specific developmental evidence. Reason: The original ARBA assignment is compatible with FOXE1 developmental biology but adds no distinct supported system or mechanism beyond the retained organ contexts. The official ontology links thyroid gland development by part_of to endocrine system development, which is_a system development. This part-whole relationship supports overlap in developmental coverage without asserting that thyroid gland development is a subclass of system development. The broad electronic row is therefore too general; its original ARBA provenance remains intact. |
| GO:0060021 roof of mouth development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Palatal development depends on appropriately controlled Foxe1 function and dosage. Reason: Two exact current mouse donor sources and their different relations are preserved: 22304410 uses acts_upstream_of_or_within, whereas 21177256 uses involved_in. The former study uses explicitly mouse ROSA26-driven TTF2 overexpression and observes persistent palatal epithelial expression with failed fusion; 21177256 reports reduced palatal/dental target transcripts after Foxe1 loss. These distinct gain/loss contexts support developmental involvement without proving apoptosis, EMT or migration as the mechanism. Human hard/soft-palate phenotypes separately corroborate the broad roof-of-mouth association; no human rescue is claimed. |
| GO:0060022 hard palate development | IMP PMID:12165566 A novel loss-of-function mutation in TTF-2 is associated wit... | KEEP AS NON CORE | Summary: Human S57N-associated hard-palate defects support a developmental context. Reason: The 12165566 report explicitly describes extensive hard and soft palate clefts in homozygous human siblings, with partial FOXE1 binding/activation impairment measured separately. This supports the hard-palate developmental association. It does not establish a hard-palate-specific direct target, osteogenic cell autonomy or complete loss of FOXE1 function. Supporting Evidence: |
| GO:0060023 soft palate development | IMP PMID:12165566 A novel loss-of-function mutation in TTF-2 is associated wit... | KEEP AS NON CORE | Summary: Human S57N-associated soft-palate defects are retained separately from hard-palate anatomy. Reason: The same 12165566 human siblings have documented soft-palate involvement as well as hard-palate clefts. The original specific anatomy is retained rather than collapsed into a broad palate term. Biochemical partial impairment supports FOXE1 dysfunction but does not resolve a soft-palate-specific transcriptional circuit or distinguish autonomous from inter-tissue developmental effects. Supporting Evidence: |
| GO:0160093 chordate pharynx development | IEP PMID:15494458 PAX8, TITF1, and FOXE1 gene expression patterns during human... | UNDECIDED | Summary: Pharyngeal FOXE1 expression is established; the exact developmental role remains uncertain. Reason: Controlled human RNA in-situ hybridization in 15494458 detects FOXE1 in oropharyngeal and related foregut epithelia. The study does not perturb FOXE1 to demonstrate chordate pharynx development. Mouse thyroid-bud rescue and human palate phenotypes concern related but distinct endpoints and are not sufficient to assign a defined pharyngeal developmental step. Preserve the original IEP assertion as an unresolved functional interpretation of genuine expression. |
| GO:1904888 cranial skeletal system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Craniofacial developmental involvement is retained with its mouse donor and human corroboration. Reason: The current mouse donor uses involved_in and cites 21177256, where Foxe1 loss reduces Msx1 dental-mesenchymal and Tgfb3 anterior-palatal epithelial transcripts. Human 12165566 hard-palate defects provide independent anatomical corroboration. These support a contextual craniofacial gene-regulatory role, not a direct measurement of mineralization or a universal skeletal program. The original human IEA, mouse accession and alternate Ensembl identifier remain unchanged. |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: A sequence-verified FOXE1 extended DNA-binding domain recognizes double-stranded DNA motifs. Reason: The original 28473536 workbook contains the FOXE1 eDBD sequence and both HT-SELEX and methyl-HT-SELEX PWM blocks. Its 134 aa match current O00358 residues 31–164 exactly. This target-specific domain experiment supports sequence-specific double-stranded DNA binding. It does not establish full-length cellular regulation, promoter occupancy, an atomic structure or a dissociation constant. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which promoter and cofactor features determine activation versus repression by endogenous human FOXE1, and how much of the ELK1-associated response requires FOXE1 DNA recognition?
Q: How do FOXE1 variants alter target regulation through protein abundance, DNA recognition and regulatory capacity, and which of those changes affect thyroid-primordium migration?
Experiment: In a human thyroid model with verified endogenous FOXE1 and ELK1 expression, compare acute FOXE1 depletion and near-endogenous rescue with a DNA-recognition mutant. Measure nascent TG/TPO transcripts and a selected ELK1-responsive target alongside matched protein abundance, nuclear access and targeted FOXE1/ELK1 chromatin occupancy. Test the relevant promoter motifs separately; distinguish occupancy and co-association from direct binary contact. Include viability and expression-level controls.
Hypothesis: FOXE1 regulatory direction depends on promoter/cofactor context rather than a uniform activation program.
Type: Targeted perturbation, transcription and promoter-occupancy assays
Experiment: Compare WT, S57N and R73S FOXE1 at matched expression in a validated thyroid epithelial differentiation model. Measure protein abundance/stability, target RNA and protein, and spatial organization or bud-movement endpoints where the model reproduces them. Use temporal induction and matched rescue to separate early tissue-patterning effects from later transcriptional responses. Treat this as a test of human conservation, not as confirmation of the published rat-cDNA mouse rescue.
Hypothesis: Variant effects on FOXE1 abundance and target regulation can be separated from secondary changes in tissue formation.
Type: Controlled variant comparison in a thyroid developmental model
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