title: Dissociation of cardiogenic and postnatal myocardial activities of GATA4.
abstract: Transcription factor GATA4 is a critical regulator of the embryonic and postnatal heart, but the mechanisms and cofactors required for its diverse functions are not fully understood. Here, we show that whereas the N-terminal domain of GATA4 is required for inducing cardiogenesis and for promoting postnatal cardiomyocyte survival, distinct residues and domains therein are necessary to mediate these effects. Cardiogenic activity of GATA4 requires a 24-amino-acid (aa) region (aa 129 to 152) which is needed for transcriptional synergy and physical interaction with BAF60c. The same region is not essential for induction of endoderm or blood cell markers by GATA4, suggesting that it acts as a cell-type-specific transcriptional activation domain. On the other hand, a serine residue at position 105, which is a known target for mitogen-activated protein kinase (MAPK) phosphorylation, is necessary for GATA4-dependent cardiac myocyte survival and hypertrophy but is entirely dispensable for GATA4-induced cardiogenesis. We find that S105 is differentially required for transcriptional synergy between GATA4 and serum response factor (SRF) but not other cardiac cofactors such as TBX5 and NKX2.5. The findings provide new insight into GATA4 mechanisms of action and suggest that distinct regulatory pathways regulate activities of GATA4 in embryonic development and postnatal hearts.
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Gallagher
authors.forename: Hiba
authors.initials: H
authors.lastname: Komati
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roy
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
authors.forename: Branko V
authors.initials: BV
authors.lastname: Latinkić
mesh_terms: D000818:Animals; D049108:Cell Enlargement; D002470:Cell Survival; D002478:Cells, Cultured; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D038081:Organogenesis; D051381:Rats; D017421:Sequence Analysis; D012694:Serine; D020825:T-Box Domain Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins
chemical_list: D050991:GATA4 Transcription Factor; C494751:GATA4 protein, Xenopus; C084365:Gata4 protein, rat; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D012694:Serine