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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Enhancer Elements, Genetic / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental / physiology*
  • Gene Library
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Mesoderm / embryology*
  • Mesoderm / metabolism
  • Microarray Analysis
  • Models, Biological
  • Molecular Sequence Data
  • Myoblasts, Cardiac / cytology*
  • Myoblasts, Cardiac / physiology
  • Proto-Oncogene Proteins / metabolism*
  • Sequence Analysis, RNA
  • T-Cell Acute Lymphocytic Leukemia Protein 1

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Proto-Oncogene Proteins
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • TAL1 protein, human

Associated data

  • GEO/GSE47085