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EMBO J. 2015 Mar 12;34(6):759-77. doi: 10.15252/embj.201490542. Epub 2015 Jan 6.

Scl binds to primed enhancers in mesoderm to regulate hematopoietic and cardiac fate divergence.

Author information

1
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA.
2
Department of Biological Chemistry, University of California, Los Angeles, CA, USA Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute Harvard Stem Cell Institute Harvard Medical School, Boston, MA, USA.
4
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, USA hmikkola@mcdb.ucla.edu.

Abstract

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.

KEYWORDS:

cardiac specification; enhancer; hematopoiesis; mesoderm diversification; transcriptional regulation

PMID:
25564442
PMCID:
PMC4369313
DOI:
10.15252/embj.201490542
[Indexed for MEDLINE]
Free PMC Article

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