SMARCA4 regulates gene expression and higherorder chromatin structure in proliferating mammary epithelial cells

A. Rasim Barutcu, Bryan R. Lajoie, Andrew J. Fritz, Rachel P. McCord, Jeffrey A. Nickerson, Andre J van Wijnen, Jane B. Lian, Janet L. Stein, Job Dekker, Gary S. Stein, Anthony N. Imbalzano

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahmarelated gene-1 SMARCA4 (also known as BRG1), the essential ATPase subunit of the mammalian SWI/SNF chromatin remodeling complex, uses the energy from ATP hydrolysis to disrupt nucleosomes at target regions. Although the transcriptional role of SMARCA4 at gene promoters is well-studied, less is known about its role in higher-order genome organization. SMARCA4 knockdown in human mammary epithelial MCF-10A cells resulted in 176 up-regulated genes, including many related to lipid and calcium metabolism, and 1292 down-regulated genes, some of which encode extracellular matrix (ECM) components that can exert mechanical forces and affect nuclear structure. ChIP-seq analysis of SMARCA4 localization and SMARCA4-bound super-enhancers demonstrated extensive binding at intergenic regions. Furthermore, Hi-C analysis showed extensive SMARCA4-mediated alterations in higher-order genome organization at multiple resolutions. First, SMARCA4 knockdown resulted in clustering of intra- And inter-subtelomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at topologically associating domain (TAD) boundaries, and SMARCA4 knockdown resulted in weakening of TAD boundary strength. Taken together, these findings provide a dynamic view of SMARCA4-dependent changes in higher-order chromatin organization and gene expression, identifying SMARCA4 as a novel component of chromatin organization.

Original languageEnglish (US)
Pages (from-to)1188-1201
Number of pages14
JournalGenome Research
Volume26
Issue number9
DOIs
StatePublished - Sep 1 2016

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Chromatin
Breast
Epithelial Cells
Gene Expression
Genes
Genome
DNA Packaging
Intergenic DNA
Chromatin Assembly and Disassembly
Nucleosomes
Telomere
Lipid Metabolism
Extracellular Matrix
Cluster Analysis
Adenosine Triphosphatases
Hydrolysis
Adenosine Triphosphate
Calcium

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Barutcu, A. R., Lajoie, B. R., Fritz, A. J., McCord, R. P., Nickerson, J. A., van Wijnen, A. J., ... Imbalzano, A. N. (2016). SMARCA4 regulates gene expression and higherorder chromatin structure in proliferating mammary epithelial cells. Genome Research, 26(9), 1188-1201. https://doi.org/10.1101/gr.201624.115

SMARCA4 regulates gene expression and higherorder chromatin structure in proliferating mammary epithelial cells. / Barutcu, A. Rasim; Lajoie, Bryan R.; Fritz, Andrew J.; McCord, Rachel P.; Nickerson, Jeffrey A.; van Wijnen, Andre J; Lian, Jane B.; Stein, Janet L.; Dekker, Job; Stein, Gary S.; Imbalzano, Anthony N.

In: Genome Research, Vol. 26, No. 9, 01.09.2016, p. 1188-1201.

Research output: Contribution to journalArticle

Barutcu, AR, Lajoie, BR, Fritz, AJ, McCord, RP, Nickerson, JA, van Wijnen, AJ, Lian, JB, Stein, JL, Dekker, J, Stein, GS & Imbalzano, AN 2016, 'SMARCA4 regulates gene expression and higherorder chromatin structure in proliferating mammary epithelial cells', Genome Research, vol. 26, no. 9, pp. 1188-1201. https://doi.org/10.1101/gr.201624.115
Barutcu AR, Lajoie BR, Fritz AJ, McCord RP, Nickerson JA, van Wijnen AJ et al. SMARCA4 regulates gene expression and higherorder chromatin structure in proliferating mammary epithelial cells. Genome Research. 2016 Sep 1;26(9):1188-1201. https://doi.org/10.1101/gr.201624.115
Barutcu, A. Rasim ; Lajoie, Bryan R. ; Fritz, Andrew J. ; McCord, Rachel P. ; Nickerson, Jeffrey A. ; van Wijnen, Andre J ; Lian, Jane B. ; Stein, Janet L. ; Dekker, Job ; Stein, Gary S. ; Imbalzano, Anthony N. / SMARCA4 regulates gene expression and higherorder chromatin structure in proliferating mammary epithelial cells. In: Genome Research. 2016 ; Vol. 26, No. 9. pp. 1188-1201.
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