Abstract
The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also required to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. These findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions.
Highlights
The emergence of individual cell types during development relies on the correct sets of genes becoming activated, while inappropriate sets of genes are simultaneously repressed
Essential Brmassociated factor (BAF) complex subunits are enriched at early stages of cardiac differentiation To gain deeper insight into how chromatin is regulated during cardiac differentiation, we analyzed our published expression datasets (Wamstad et al, 2012) to identify the expression patterns of known chromatin regulators
We selected genes annotated with involvement in chromatin remodeling (Gene ontology category GO0006338) or covalent chromatin modification (GO00016569), and clustered their gene expression patterns across four stages of cardiomyocyte differentiation: embryonic stem cells (ESCs), mesodermal precursors (MES), cardiac precursors (CP) or functional cardiomyocytes (CMs)
Summary
The emergence of individual cell types during development relies on the correct sets of genes becoming activated, while inappropriate sets of genes are simultaneously repressed. This process is achieved in large part by modifying chromatin structure, which packages the genome within the nucleus and affects multiple facets of gene regulation (Ho and Crabtree, 2010). Received 25 February 2014; Accepted 27 February 2015 embryonic stem cells (ESCs), PRC2 targets a broad group of developmental regulators for silencing to ensure appropriate lineagespecific gene expression (Surface et al, 2010). Enhancer occupancy by H3K27ac is highly dynamic during cellular differentiation, yet the factors that modulate H3K27ac occupancy at promoters and enhancers remain poorly understood
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