GATA4 (human, P43694) review notes

Automated deep research was unavailable for this run (falcon 402, OpenAI 401), so no
-deep-research-<provider>.md file exists. These notes were compiled manually from cached
publications in publications/, the UniProt record, and PubMed searches (E-utilities).

Identity and domains

• GATA zinc-finger transcription factor, 442 aa; two GATA-type zinc fingers (UniProt ZN_FING 217-241
  N-terminal, 271-295 C-terminal), N-terminal transactivation domains, C-terminal NLS region.
• UniProt: "Transcriptional activator that binds to the consensus sequence 5'-AGATAG-3' and plays a key
  role in cardiac development and function". Nuclear.
• C-terminal finger = DNA recognition; N-terminal finger stabilises binding and binds FOG cofactors
  PMID:21220346.

Molecular function

• Sequence-specific Pol II cis-regulatory binding and activation: binds GATA element of AMH promoter
  (EMSA) and transactivates PMID:21220346.
• Patient mutations reduce DNA binding and transcriptional activity PMID:24000169;
  PMID:12845333.
• Pioneer-like activity: GATA-4 binds sites in linker-histone-compacted nucleosome arrays and opens local
  chromatin without ATP-dependent remodelers PMID:11864602.
• Genome-wide: co-occupies cardiac enhancers with TBX5 in human iPSC-cardiomyocytes; G296S disrupts TBX5
  recruitment to super-enhancers; also required for repression of non-cardiac genes PMID:27984724.

Partner TFs and cofactors (combinatorial complexes)

• NKX2-5: mutual cofactors, physical interaction via GATA4 C-terminal finger + extension and NKX2-5
  homeodomain; synergistic activation of NPPA/ANF PMID:9312027;
  PMID:9584153. Consistent with the
  NKX2-5 (human) and Nkx2-5 (mouse) reviews, which use GO:0061629 for this binding.
• TBX5: PMID:12845333.
• SMAD4: co-SMAD binding; cooperative activation of Id2 in endocardial cushion PMID:21330551.
• ZFPM2/FOG2 (N-terminal finger): required for heart and gonad development; Gata4 V217G knock-in
  (FOG-binding defective) gives DORV and valve defects PMID:11297508 and gonad failure with low Sry PMID:12223418.
• NR5A1/SF-1: synergistic activation of AMH PMID:21220346.
• KLF13 PMID:17053787; HEY/HRT bHLH repressors bind GATA4 and inhibit it [PMID:15485867, PMID:16199874].
• BRD4, GLYR1, SMARCC1 from AP-MS interactome in cardiac progenitors PMID:35182466.

Biological roles

• Heart: Gata4-/- mouse embryos lack a ventral heart tube because of failed ventral folding, but
  cardiomyocytes do differentiate; GATA4 "is not essential for the specification of the cardiac cell lineages"
  PMID:9136932; PMID:9136933.
  So "cardiac cell fate specification/commitment" should not be asserted strongly for mammalian GATA4
  (redundancy with GATA5/6). Myocardial Gata4 controls cardiomyocyte proliferation, RV and AV canal
  morphogenesis PMID:15902305. Dosage-sensitive: 70% reduction gives CAVC, DORV, hypoplastic myocardium
  PMID:15464586. Human heterozygous mutations: ASD, VSD, AVSD, TOF, BAV [PMID:12845333, PMID:24000169, PMID:29325903, PMID:21330551].
• Endoderm: foregut morphogenesis defect in null PMID:9136932; liver bud expansion and ventral pancreas require GATA4
  (liver effect likely non-cell-autonomous via septum transversum) PMID:17451603. Intestinal
  terminal differentiation (Xenopus/chick/human cell data) PMID:9566909.
• Gonad: GATA4-FOG2 required for Sry expression and testis differentiation in mouse PMID:12223418;
  human G221R (N-finger) mutation causes 46,XY DSD PMID:21220346.

Curation decisions summary

• Core: GO:0000981 / GO:0000978 / GO:0045944 in heart development (matches module annoton GO:0000981 in
  GO:0007507); partner-TF binding GO:0061629; testis development as second core role.
• Generic protein binding IPI rows -> MODIFY to GO:0061629 (TF partners) or GO:0001221 (FOG2; BRD4/GLYR1/SMARCC1).
• Response-to-X and stress/tissue-repair IEA rows from rodent orthologs -> mostly MARK_AS_OVER_ANNOTATED.
• PMID:20585342 (SNP association with acamprosate relapse) does not support "response to xenobiotic stimulus" -> REMOVE.
• PMID:28473536 methyl-SELEX: GATA4 not mentioned in cached text (supplementary data); accepted deferring to curator.