Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling

Autor: John E. Lazar, Sandra Stehling-Sun, Vivek Nandakumar, Hao Wang, Daniel R. Chee, Nicholas P. Howard, Reyes Acosta, Douglass Dunn, Morgan Diegel, Fidencio Neri, Andres Castillo, Sean Ibarrientos, Kristen Lee, Ninnia Lescano, Ben Van Biber, Jemma Nelson, Jessica Halow, Richard Sandstrom, Daniel Bates, Fyodor D. Urnov, Alister P.W. Funnell, John A. Stamatoyannopoulos
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Cell Reports, Vol 31, Iss 8, Pp - (2020)
Druh dokumentu: article
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2020.107676
Popis: Summary: The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA.
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