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SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

ABSTRACT: The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahma related 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- sub-telomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at TAD (Topologically Associating Domain) 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74716 | GEO | 2016/06/02

SECONDARY ACCESSION(S): PRJNA301233

REPOSITORIES: GEO

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SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

Project description:The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahma related 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- sub-telomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at TAD (Topologically Associating Domain) 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. Hi-C and RNA-seq experiments were conducted in MCF-10A shSCRAM and shSMARCA4 cells. SMARCA4 ChIP-seq was conducted in wildtype MCF-10A cells.

2016-06-02 | E-GEOD-74716 | biostudies-arrayexpress

SCC1 interaction proteomics in Saccharomyces cerevisiae

Project description:FACT mediates cohesin function on chromatin Cohesin is a key regulator of genome architecture with roles in sister chromatid cohesion and the organisation of higher-order structures during interphase and mitosis. The recruitment and mobility of cohesin complexes on DNA are restricted by nucleosomes. Here we show that cohesin role in chromosome organization requires the histone chaperone FACT. Depletion of FACT in metaphase cells affects cohesin stability on chromatin reducing its accumulation at pericentric regions and binding on chromosome arms. Using Hi-C, we show that cohesin-dependent TAD (Topological Associated Domains)-like structures in G1 and metaphase chromosomes are disrupted in the absence of FACT. Surprisingly, sister chromatid cohesion is intact in FACT-depleted cells, although chromosome segregation failure is observed. Our results uncover a role for FACT in genome organisation by facilitating cohesin dependent compartmentalization of chromosomes into loop domains.

2019-10-03 | PXD014896 | Pride

TOPORS, a tumor suppressor protein, maintains higher-order chromatin organization in mouse hepatocytes [H3K9me3 ChIP-seq]

Project description:Within mammalian nuclear space, chromosomes are hierarchically folded into active (A) and inactive (B) compartments composed of topologically associating domains (TADs). Genomic regions interact with nuclear lamina, termed lamina-associated domains (LADs), associated with transcriptional repression. However, the molecular mechanisms underlying these 3D chromatin architectures remain undeciphered. Here, we demonstrate the role of a potential tumor suppressor, TOP1 Binding Arginine/Serine Rich Protein (TOPORS), in genome organization. Topors knockdown in mouse hepatocytes results in cell proliferation and migration promotion, as well as arrest in the S phase of the cell cycle. RNA-seq analysis shows that 373 genes are up-regulated, some of which are associated with nuclear structure, and 316 genes exhibit down-regulated, many related to metabolic process. Chromatin accessibility is inclined to alter in the intergenic regions, including enhancers. Chromatin-lamina interactions decrease globally, and the coverage of LADs reduces from 53.31% to 46.52%. Furthermore, Topors knockdown leads to significantly increasing interactions between A and B compartments in cis and in trans. Correspondingly, strength of TAD boundaries located at A/B borders is weakened. Collectively, our data reveal that TOPORS functions as a regulator in chromosome folding, providing novel insights into the architectural role of tumor suppressors in higher-order genome organization.

2020-06-24 | GSE143886 | GEO

TOPORS, a tumor suppressor protein, maintains higher-order chromatin organization in mouse hepatocytes [HiC]

2020-06-24 | GSE134621 | GEO

TOPORS, a tumor suppressor protein, maintains higher-order chromatin organization in mouse hepatocytes [H3K27ac ChIP]

2020-06-24 | GSE134620 | GEO

TOPORS, a tumor suppressor protein, maintains higher-order chromatin organization in mouse hepatocytes [ATAC-seq]

2020-06-24 | GSE134619 | GEO

TOPORS, a tumor suppressor protein, maintains higher-order chromatin organization in mouse hepatocytes [RNA-seq]

2020-06-24 | GSE134623 | GEO

TOPORS, a tumor suppressor protein, maintains higher-order chromatin organization in mouse hepatocytes [PML ChIP-seq]

2020-06-24 | GSE134622 | GEO

TOPORS, a tumor suppressor protein, maintains higher-order chromatin organization in mouse hepatocytes [DamID]

2020-06-24 | GSE133224 | GEO

Tetrahymena thermophila macronucleus chromosomes originate from chromatin breakage sequence defined TAD-like structures in micronucleus chromosomes

Project description:The somatic macronucleus (MAC) and germline micronucleus (MIC) of Tetrahymena thermophila differ in chromosome numbers, sizes, functions, transcriptional activities, and cohesin complex location. However, the higher-order chromatin organization in T. thermophila which contains both cohesin free MAC and cohesin located MIC are largely unknown. Here, we examined the higher-order chromatin organization in the two distinct nuclei of T. thermophila using the Hi-C and HiChIP. Interestingly, we found that the crescent MIC possess specific chromosome interaction pattern. All the telomeres or centromeres on the five MIC chromosomes clustering together, respectively, which could help to identify the midpoints of centromeres in the MIC. We found the transcriptionally active MAC chromosomes lack A/B compartments, topologically associating domains (TADs) and chromatin loops. The transcriptionally inert MIC chromosomes also without A/B compartments and chromatin loops, but have TAD-like structures. The boundaries of the TAD-like structures in the MIC were highly consistent with the chromatin breakage sequence (CBS) sites, suggesting that each TAD-like structure of the MIC chromosomes develops into one MAC chromosome during MAC development during conjugation. Overall, we revealed the higher-order chromatin organization in the T. thermophila and found the chromatin structures might play important roles during the development of the MAC chromosomes.

2020-02-21 | GSE140429 | GEO

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