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

Journal Article · · Genome Research
 [1];  [1];  [1];  [2];  [3];  [4];  [5];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [5];  [4];  [6];  [6];  [6]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division
  2. USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
  3. USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of Cambridge (United Kingdom). NHS Trust. Addenbrooke's Hospital
  4. Harvard Medical School, Boston, MA (United States); Massachusetts General Hospital, Boston, MA (United States). HHMI. Dept. of Pathology
  5. Univ. of California, San Diego, La Jolla, CA (United States). School of Medicine. Ludwig Inst. for Cancer Research
  6. 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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Early patterning and specification of cardiac progenitors in gastrulating mesoderm journal October 2014
Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes journal December 2015
Chromatin-remodelling factor Brg1 regulates myocardial proliferation and regeneration in zebrafish journal December 2016
Hierarchical regulation of the genome: global changes in nucleosome organization potentiate genome response journal January 2016
Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment journal July 2017
Mammalian SWI/SNF collaborates with a polycomb-associated protein to regulate male germ line transcription in the mouse posted_content November 2018
Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes text January 2015
A Discrete Transition Zone Organizes the Topological and Regulatory Autonomy of the Adjacent Tfap2c and Bmp7 Genes journal January 2015
Brg1 controls neurosensory cell fate commitment and differentiation in the mammalian inner ear posted_content January 2018
Brg1 modulates enhancer activation in mesoderm lineage commitment journal March 2015
Epigenetic Regulation by BAF Complexes Limits Neural Stem Cell Proliferation by Suppressing Wnt Signaling in Late Embryonic Development journal June 2018
Hierarchical cooperation of transcription factors from integration analysis of DNA sequences, ChIP-Seq and ChIA-PET data journal May 2019
The chromatin-remodeling enzyme BRG1 promotes colon cancer progression via positive regulation of WNT3A journal November 2016
Dynamic BAF chromatin remodeling complex subunit inclusion promotes temporally distinct gene expression programs in cardiogenesis journal February 2019
The connection between BRG1, CTCF and topoisomerases at TAD boundaries journal January 2017
SWI/SNF interacts with cleavage and polyadenylation factors and facilitates pre-mRNA 3′ end processing journal May 2018
Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma journal December 2015
Elucidating the genetic basis of an oligogenic birth defect using whole genome sequence data in a non-model organism, Bubalus bubalis journal January 2017
SWI/SNF regulates half of its targets without the need of ATP-driven nucleosome remodeling by Brahma journal May 2018
Deletion of Brg1 causes abnormal hair cell planer polarity, hair cell anchorage, and scar formation in mouse cochlea journal June 2016
CIC is a Critical Regulator of Neuronal Differentiation posted_content January 2019
Mammalian SWI/SNF collaborates with a polycomb-associated protein to regulate male germ line transcription in the mouse journal January 2019
The Chromatin Environment Around Interneuron Genes in Oligodendrocyte Precursor Cells and Their Potential for Interneuron Reprograming journal August 2019
Elucidating the genetic basis of an oligogenic birth defect using whole genome sequence data in a non-model organism, Bubalus bubalis posted_content June 2016
Noncommutative Biology: Sequential Regulation of Complex Networks journal August 2016