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Genome Res. 2014 Jun;24(6):920-9. doi: 10.1101/gr.168930.113. Epub 2014 Apr 21.

Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis.

Author information

1
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA;
2
US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA;
3
US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA; Addenbrooke's Hospital, Cambridge University NHS Trust, Cambridge CB2 0QQ, United Kingdom;
4
HHMI and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA;
5
Ludwig Institute for Cancer Research, UCSD School of Medicine, La Jolla, California 92093, USA.
6
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA; US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA;

Abstract

The SMARCA4 (also known as BRG1 in humans) chromatin remodeling factor is critical for establishing lineage-specific chromatin states during early mammalian development. However, the role of SMARCA4 in tissue-specific gene regulation during embryogenesis remains poorly defined. To investigate the genome-wide binding landscape of SMARCA4 in differentiating tissues, we engineered a Smarca4(FLAG) knock-in mouse line. Using ChIP-seq, we identified ∼51,000 SMARCA4-associated regions across six embryonic mouse tissues (forebrain, hindbrain, neural tube, heart, limb, and face) at mid-gestation (E11.5). The majority of these regions was distal from promoters and showed dynamic occupancy, with most distal SMARCA4 sites (73%) confined to a single or limited subset of tissues. To further characterize these regions, we profiled active and repressive histone marks in the same tissues and examined the intersection of informative chromatin states and SMARCA4 binding. This revealed distinct classes of distal SMARCA4-associated elements characterized by activating and repressive chromatin signatures that were associated with tissue-specific up- or down-regulation of gene expression and relevant active/repressed biological pathways. We further demonstrate the predicted active regulatory properties of SMARCA4-associated elements by retrospective analysis of tissue-specific enhancers and direct testing of SMARCA4-bound regions in transgenic mouse assays. Our results indicate a dual active/repressive function of SMARCA4 at distal regulatory sequences in vivo and support its role in tissue-specific gene regulation during embryonic development.

PMID:
24752179
PMCID:
PMC4032856
DOI:
10.1101/gr.168930.113
[Indexed for MEDLINE]
Free PMC Article
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