Journal
EMBO JOURNAL
Volume 34, Issue 6, Pages 759-777Publisher
WILEY
DOI: 10.15252/embj.201490542
Keywords
cardiac specification; enhancer; hematopoiesis; mesoderm diversification; transcriptional regulation
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Funding
- California Institute for Regenerative Medicine (CIRM) New Faculty Award [RN1-00557]
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA Research Award
- American Heart Association [14GRNT20480340]
- Leukemia Lymphoma Society Scholar Award [20103778]
- Leukemia Lymphoma Society postdoctoral fellowship [57537-13]
- European Union through the European Social Fund [MJD284]
- government of P.R.C through the State Scholarship Fund [2011624028]
- HFSP
- American Society of Hematology
- NIH/NHLBI [T32 HL69766]
- [P30DK049216]
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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.
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