FOXJ3

UniProt ID: A0A9L0JKH1
Organism: Equus asinus
Review Status: COMPLETE
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Gene Description

FOXJ3 (forkhead box J3) is a nuclear forkhead (FOX) family transcription factor of the FOXJ2/FOXJ3 group. Its winged-helix fork-head domain binds forkhead consensus sites in cis-regulatory regions of RNA polymerase II-transcribed genes, and a carboxy-terminal region carries its transcriptional activation activity. In mouse, Foxj3 binds a conserved forkhead site in the skeletal muscle enhancer of Mef2c and activates it, and loss of Foxj3 reduces slow-twitch (type I) myofibers and impairs muscle regeneration; conditional deletion causes male sterility through loss of spermatogonia and meiotic arrest of spermatocytes; adipose deletion impairs brown-fat thermogenesis; and in developing cortex FOXJ3 regulates Pten and neuronal specification, with heterozygous human variants associated with focal epilepsy and focal cortical dysplasia. Xenopus Foxj3 represses Activin/Nodal- and BMP-responsive transcription. This donkey entry (580 aa) is an alternative transcript of the FOXJ3 gene; it is identical to the 623-aa full-length donkey model except that it lacks a 43-residue internal segment C-terminal to the intact fork-head domain.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
IEA
GO_REF:0000118 		ACCEPT
Summary: TreeGrafter transfer from PANTHER node PTN000215310; the donkey protein is in subfamily PTHR46078:SF3 (FORKHEAD BOX PROTEIN J3) together with human Q9UPW0 and mouse Q8BUR3. Mouse Foxj3 binds a conserved forkhead site in the Mef2c skeletal-muscle enhancer (ChIP and reporter mutagenesis), and the fork-head domain of this donkey isoform is identical to the full-length donkey model and gap-free against human.
Reason: Sequence-specific binding of cis-regulatory sites of Pol II genes is the core DNA-binding activity of FOXJ3, experimentally shown for the mouse ortholog (same PANTHER subfamily). The isoform deletion (full-length residues 211-253) lies outside the fork-head domain.
Supporting Evidence:
PMID:19914232
Foxj3 transcriptionally activates the Mef2c gene in a dose dependent fashion and binds to the conserved FBS
file:EQUAS/FOXJ3/FOXJ3-bioinformatics/RESULTS-rereview.md
The human fork-head DNA_BIND feature (77-168) aligns gap-free to both donkey models
file:EQUAS/FOXJ3/FOXJ3-bioinformatics/RESULTS.md
The fork-head DNA-binding domain (donkey 78-173) aligns without gaps
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
IEA
GO_REF:0000118 		ACCEPT
Summary: TreeGrafter transfer from PTN000215310 (PTHR46078:SF3). Mouse Foxj3 activates the Mef2c enhancer via its forkhead site, and its C-terminal region (after residue 176) is required for Gal4-fusion transactivation; Xenopus Foxj3 acts as a repressor of TGF-beta-responsive transcription.
Reason: Core molecular function. Kept at the activator/repressor-neutral level because FOXJ3 orthologs have been described both as activators (mouse Mef2c, Pgc1a/Ucp1, Pten) and as a repressor (Xenopus), and the donkey isoform lacks a segment (full-length 211-253) of the C-terminal region in which the activation domain lies, so activator activity of this particular isoform is untested.
Supporting Evidence:
PMID:19914232
Foxj3 transcriptionally activates the Mef2c gene in a dose dependent fashion and binds to the conserved FBS
PMID:19914232
The resulting mutant Foxj3 allele produces a transcript that encodes exons 1–5 (1–176 amino acids) of the Foxj3 protein that lacks a transcriptional activation domain.
PMID:40522413
Foxj3 was found to regulate negatively the transcription of target genes induced by Activin/Nodal or BMP signal in Xenopus embryos
GO:0003677 DNA binding
IEA
GO_REF:0000104 		TOO GENERAL
Summary: UniRule DNA binding, from the fork-head domain. True but uninformative.
Reason: Entailed by the accepted RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978) on this same gene product.
GO:0003700 DNA-binding transcription factor activity
IEA
GO_REF:0000002 		TOO GENERAL
Summary: InterPro2GO DNA-binding transcription factor activity from the fork-head domain signatures.
Reason: Correct but entailed by the accepted, more specific RNA polymerase II-specific transcription factor activity (GO:0000981) on this gene product.
GO:0005634 nucleus
IEA
GO_REF:0000120 		ACCEPT
Summary: Nucleus, combined from SubCell, the PANTHER node and UniRule. Mouse Foxj3 Gal4 fusions, including the full-length protein, localize to the nuclear compartment.
Reason: Expected and experimentally observed (mouse ortholog, same subfamily) location of a forkhead transcription factor; the fork-head domain is intact in this isoform.
Supporting Evidence:
PMID:19914232
Overexpression of the full-length Gal4-Foxj3 and the truncated transcripts were expressed in the nuclear compartment
file:EQUAS/FOXJ3/FOXJ3-bioinformatics/human-Q9UPW0-uniprot.txt
SUBCELLULAR LOCATION: Nucleus
GO:0006355 regulation of DNA-templated transcription
IEA
GO_REF:0000002 		TOO GENERAL
Summary: InterPro2GO regulation of DNA-templated transcription.
Reason: Entailed by the accepted regulation of transcription by RNA polymerase II (GO:0006357) on this gene product.
GO:0006357 regulation of transcription by RNA polymerase II
IEA
GO_REF:0000118 		ACCEPT
Summary: TreeGrafter transfer from PTN000215310 (PTHR46078:SF3).
Reason: The process the core DNA-binding transcription factor activity serves. Positive regulation is documented for mouse targets and negative regulation for Xenopus TGF-beta-responsive genes, so the sign-neutral family-level term is the appropriate claim for this isoform.
Supporting Evidence:
PMID:19914232
Foxj3 transcriptionally activates the Mef2c gene in a dose dependent fashion and binds to the conserved FBS
PMID:40522413
Foxj3 was found to regulate negatively the transcription of target genes induced by Activin/Nodal or BMP signal in Xenopus embryos
GO:0043565 sequence-specific DNA binding
IEA
GO_REF:0000002 		TOO GENERAL
Summary: InterPro2GO sequence-specific DNA binding from the fork-head domain signatures.
Reason: Correct but entailed by the accepted RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978) on this gene product.

Core Functions

Forkhead-domain, sequence-specific RNA polymerase II transcription factor that binds forkhead sites in cis-regulatory DNA in the nucleus and regulates target-gene transcription (for the mouse ortholog, activation of Mef2c).

Molecular Function:
DNA-binding transcription factor activity, RNA polymerase II-specific
Directly Involved In:
regulation of transcription by RNA polymerase II
Cellular Locations:
nucleus
Supporting Evidence:
  • PMID:19914232
    Foxj3 transcriptionally activates the Mef2c gene in a dose dependent fashion and binds to the conserved FBS
  • file:EQUAS/FOXJ3/FOXJ3-bioinformatics/RESULTS-rereview.md
    The human fork-head DNA_BIND feature (77-168) aligns gap-free to both donkey models
  • file:EQUAS/FOXJ3/FOXJ3-bioinformatics/RESULTS.md
    The fork-head DNA-binding domain (donkey 78-173) aligns without gaps

References

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Suggested Questions for Experts

Q: Is the donkey FOXJ3 transcript lacking full-length residues 211-253 (A0A9L0JKH1) expressed, and does the missing segment, which lies in the C-terminal region that carries transactivation activity in mouse Foxj3, alter activation of targets such as MEF2C?

Q: Should the human IDA DNA-binding transcription activator activity be propagated across the FOXJ3 subfamily, given the repressor activity reported for Xenopus Foxj3?

Q: Do the muscle fiber-type, spermatogenesis and brown-fat roles shown by mouse Foxj3 knockouts hold in equids?

Suggested Experiments

Experiment: RT-PCR across the exon encoding full-length residues 211-253 in donkey muscle and testis to test whether the skipping isoform is expressed, followed by Mef2c-enhancer reporter assays comparing the 580- and 623-residue isoforms.

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · FOXJ3-protnlm-predictions-review.yaml · Review status: COMPLETE

Assessment of the 2 ProtNLM2 GO predictions for donkey FOXJ3 (A0A9L0JKH1, DONKEY40 cohort), using the reviewed human ortholog Q9UPW0, experimental evidence on mouse Foxj3 (PMID:19914232), and a donkey-human alignment (98.1% identity; fork-head domain aligned without gaps). Both predictions (sequence-specific DNA binding; DNA-binding transcription factor activity) are biologically correct. Each exact term is already in donkey GOA through InterPro2GO, and donkey GOA also holds the more specific RNA polymerase II-specific forms from TreeGrafter, so both are scored LSP. The ProtNLM2 evidence records tie these predictions to those TreeGrafter terms. ProtNLM2 emitted no function text or subcellular-location statement for this accession in the snapshot.

Source documents: projects/PROTNLM_EVALUATION/donkey40/donkey40-predictions.tsv · projects/PROTNLM_EVALUATION/donkey40/donkey40-evidence.tsv · genes/EQUAS/FOXJ3/FOXJ3-goa.tsv · genes/EQUAS/FOXJ3/FOXJ3-bioinformatics/RESULTS.md · genes/EQUAS/FOXJ3/FOXJ3-bioinformatics/human-Q9UPW0-uniprot.txt

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0043565 sequence-specific DNA binding GO_MF
LSP — Less precise than existing annotation Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: The donkey protein carries a complete fork-head winged-helix DNA-binding domain that aligns without gaps to human FOXJ3 (98.1% identity), and mouse Foxj3 binds a conserved forkhead binding site in the Mef2c skeletal muscle enhancer. The prediction is therefore correct. The exact term is already present in donkey GOA (InterPro2GO), and donkey GOA also has the more specific RNA polymerase II cis-regulatory region sequence-specific DNA binding (TreeGrafter), which the ProtNLM2 evidence record cites. The prediction is less precise than existing annotation. Training-set membership is unknown. This accession is an exon-skipping isoform lacking full-length (A0A8C4PFN5) residues 211-253, a segment outside the fork-head domain with no mapped functional feature; the fork-head domain (78-173) is identical to the full-length model, so the product retains what this activity needs.
Supporting Evidence:
GO:0003700 DNA-binding transcription factor activity GO_MF
LSP — Less precise than existing annotation Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: FOXJ3 is a forkhead transcription factor; the mouse ortholog activates Mef2c transcription through a conserved forkhead binding site in its enhancer (PMID:19914232). The donkey protein is 98.1% identical to human FOXJ3 with an intact fork-head domain, so the prediction is correct. The exact term is in donkey GOA (InterPro2GO) and the more specific DNA-binding transcription factor activity, RNA polymerase II-specific is in donkey GOA from TreeGrafter; the prediction is less precise than that. Training-set membership is unknown. This accession is an exon-skipping isoform lacking full-length (A0A8C4PFN5) residues 211-253, a segment outside the fork-head domain with no mapped functional feature; the fork-head domain (78-173) is identical to the full-length model, so the product retains what this activity needs.
Supporting Evidence:

Deep Research

Cyberian

(FOXJ3-deep-research-cyberian.md)

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📚 Additional Documentation

Notes

(FOXJ3-notes.md)

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Bioinformatics Results

(RESULTS.md)

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📄 View Raw YAML

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