Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division
- USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
- USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of Cambridge (United Kingdom). NHS Trust. Addenbrooke's Hospital
- Harvard Medical School, Boston, MA (United States); Massachusetts General Hospital, Boston, MA (United States). HHMI. Dept. of Pathology
- Univ. of California, San Diego, La Jolla, CA (United States). School of Medicine. Ludwig Inst. for Cancer Research
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
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 Smarca4FLAG 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 midgestation (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.
- Research Organization:
- Univ. of California, Oakland, CA (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
- Grant/Contract Number:
- AC02-05CH11231
- OSTI ID:
- 1625630
- Journal Information:
- Genome Research, Vol. 24, Issue 6; ISSN 1088-9051
- Publisher:
- Cold Spring Harbor Laboratory PressCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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