GATA6 regulates WNT and BMP programs to pattern precardiac mesoderm during the earliest stages of human cardiogenesis.

TitleGATA6 regulates WNT and BMP programs to pattern precardiac mesoderm during the earliest stages of human cardiogenesis.
Publication TypeJournal Article
Year of Publication2025
AuthorsBisson JA, Gordillo M, Kumar R, de Silva N, Yang E, Banks KM, Shi Z-D, Lee K, Yang D, Chung WK, Huangfu D, Evans T
JournalElife
Volume13
Date Published2025 Mar 13
ISSN2050-084X
KeywordsBone Morphogenetic Proteins, Cell Differentiation, GATA6 Transcription Factor, Gene Expression Regulation, Developmental, Heart, Human Embryonic Stem Cells, Humans, Mesoderm, Myocytes, Cardiac, Organogenesis, Wnt Proteins
Abstract

Haploinsufficiency for GATA6 is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers, suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hr of cardiac differentiation is sufficient to partially rescue CPC and CM defects in GATA6 heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by human GATA6 mutations.

DOI10.7554/eLife.100797
Alternate JournalElife
PubMed ID40080060
PubMed Central IDPMC11906159
Grant ListNYSTEM C029567 / / New York State Department of Health - Wadsworth Center /
2016-004 / / Starr Foundation /
P01HD068250 / NH / NIH HHS / United States
R35 HL135778 / HL / NHLBI NIH HHS / United States
T32 GM152349 / GM / NIGMS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R35135778 / NH / NIH HHS / United States
F32HL152575 / NH / NIH HHS / United States
F32 HL152575 / HL / NHLBI NIH HHS / United States
T32GM007739 / NH / NIH HHS / United States
P01 HD068250 / HD / NICHD NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
R01DK096239 / NH / NIH HHS / United States
P30CA008748 / NH / NIH HHS / United States
R01 DK096239 / DK / NIDDK NIH HHS / United States