Scl binds to primed enhancers in mesoderm to regulate hematopoietic and cardiac fate divergence.
Scl/Tal1 confers hemogenic competence and prevents ectopic cardiomyogenesis in embryonic endothelium by unknown mechanisms. We discovered that Scl binds to hematopoietic and cardiac enhancers that become epigenetically primed in multipotent cardiovascular mesoderm, to regulate the divergence of hematopoietic and cardiac lineages. Scl does not act as a pioneer factor but rather exploits a pre-established epigenetic landscape. As the blood lineage emerges, Scl binding and active epigenetic modifications are sustained in hematopoietic enhancers, whereas cardiac enhancers are decommissioned by removal of active epigenetic marks. Our data suggest that, rather than recruiting corepressors to enhancers, Scl prevents ectopic cardiogenesis by occupying enhancers that cardiac factors, such as Gata4 and Hand1, use for gene activation. Although hematopoietic Gata factors bind with Scl to both activated and repressed genes, they are dispensable for cardiac repression, but necessary for activating genes that enable hematopoietic stem/progenitor cell development. These results suggest that a unique subset of enhancers in lineage-specific genes that are accessible for regulators of opposing fates during the time of the fate decision provide a platform where the divergence of mutually exclusive fates is orchestrated.
['Org|Tõnis|T|', 'Duan|Dan|D|', 'Ferrari|Roberto|R|', 'Montel-Hagen|Amelie|A|', 'Van Handel|Ben|B|', 'Kerényi|Marc A|MA|', 'Sasidharan|Rajkumar|R|', 'Rubbi|Liudmilla|L|', 'Fujiwara|Yuko|Y|', 'Pellegrini|Matteo|M|', 'Orkin|Stuart H|SH|', 'Kurdistani|Siavash K|SK|', 'Mikkola|Hanna Ka|HK|']
D051792:Basic Helix-Loop-Helix Transcription Factors D002454:Cell Differentiation D002478:Cells, Cultured D047369:Chromatin Immunoprecipitation D004742:Enhancer Elements, Genetic D020869:Gene Expression Profiling D018507:Gene Expression Regulation, Developmental D015723:Gene Library D006412:Hematopoietic Stem Cells D006801:Humans D008648:Mesoderm D046228:Microarray Analysis D008954:Models, Biological D008969:Molecular Sequence Data D032386:Myoblasts, Cardiac D011518:Proto-Oncogene Proteins D017423:Sequence Analysis, RNA D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
enhancer cardiac specification hematopoiesis mesoderm diversification transcriptional regulation