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RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.

ABSTRACT: RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. About 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1-depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. These results suggest an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75070 | GEO | 2016/08/23

SECONDARY ACCESSION(S): PRJNA302327

REPOSITORIES: GEO

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RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.

Project description:RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. About 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1-depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. These results suggest an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells. Hi-C and RNA-seq experiments were conducted in MCF-7 shNS and shRUNX1 cells. RUNX1 ChIP-seq was conducted in wildtype MCF-7 cells.

2016-08-23 | E-GEOD-75070 | biostudies-arrayexpress

Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells

Project description:Background: Higher-order chromatin structure is often perturbed in cancer and other pathological states. Although several genetic and epigenetic differences have been charted between normal and breast cancer tissues, changes in higher-order chromatin organization during tumorigenesis have not been fully explored. To probe the differences in higher-order chromatin structure between mammary epithelial and breast cancer cells, we performed Hi-C analysis on MCF-10A mammary epithelial and MCF-7 breast cancer cell lines. Results: Our studies reveal that the small, gene-rich chromosomes chr16 through chr22 in the MCF-7 breast cancer genome display decreased interaction frequency with each other compared to the inter-chromosomal interaction frequency in the MCF-10A epithelial cells. Interestingly, this finding is associated with a higher occurrence of open compartments on chr16-22 in MCF-7 cells. Pathway analysis of the MCF-7 up-regulated genes located in altered compartment regions on chr16-22 reveals pathways related to repression of WNT signalling. There are also differences in intra-chromosomal interactions between the cell lines; telomeric and sub-telomeric regions in the MCF-10A cells display more frequent interactions than are observed in the MCF-7 cells. Conclusions: We show evidence of an intricate relationship between chromosomal organization and gene expression between epithelial and breast cancer cells. Importantly, this work provides a genome-wide view of higher-order chromatin dynamics and a resource for studying higher-order chromatin interactions in two cell lines commonly used to study the progression of breast cancer. Hi-C experiments were conducted in MCF-7 and MCF-10A parental cells. The RNA-seq data associated with this study is deposited under the GEO accession number GSE71862.

2015-09-02 | E-GEOD-66733 | biostudies-arrayexpress

Rad21 is the core subunit of cohesin complex in directing genome organization

Project description:In eukaryotes, the nuclear chromatin in the interphase is a hierarchical organization. Previous studies have suggested that cohesin-DNA interactions play important architectural functions for chromatin structure in the interphase. In this study, we applied super-resolution imaging, single-molecule imaging to measure the distribution of cohesin subunits. Hi-C and RNA-seq were used to reveal the 3D genome structures alterations and the relationship with breast cancer upon Rad21 up-regulation. Hi-C experiment showed that the contact frequency of short distance was increased while that of long distance was decreased in the absence of Rad21 up-regulation. Chromatin interactions between A and B compartments increased and compartmentalization strength was reduced significantly upon Rad21 up-regulation. Correspondingly, accumulated contacts were shown at TAD corners and inter-TAD interactions increased. These observations support cohesin loop extrusion model and lead us to propose the unique role of Rad21-loader interaction in cohesin loading and further cohesin extrusion. Moreover, we combined transcriptome changes and chromatin structure alterations upon Rad21 up-regulation and revealed the correlation between Rad21 and breast cancer by affecting chromatin architecture.

2022-05-01 | GSE183186 | GEO

Homo sapiens

Project description:RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.

| PRJNA302327 | ENA

Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells

2015-09-02 | GSE66733 | GEO

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

A prostate cancer chromatin interaction map

Project description:A high-resolution 3D epigenomic map reveals insights into the creation of the prostate cancer transcriptome Prostate cancer (PCa) is the leading cancer among men in the United States. To understand gene regulation in 3D, chromatin interactions in prostate cancer cell is measured using in situ Hi-C. To better understand the impact of chromatin structure on regulation of the prostate cancer transcriptome, we developed high-resolution chromatin interaction maps in normal and prostate cancer cells using in situ Hi-C. By combining the in situ Hi-C data with active and repressive histone marks, CTCF binding sites, nucleosome-depleted regions, and transcriptome profiling, we identified topologically associating domains that changed in size and epigenetic states between normal and prostate cancer cells. Moreover, we identified normal and prostate cancer-specific enhancer-promoter loops and involved transcription factors. This creation of 3D epigenomic maps will enable a better understanding of prostate cancer biology and mechanisms of gene regulation.

2019-09-13 | GSE118629 | GEO

Deterioration of multi-level 3D genome organization during breast cancer progression

Project description:Breast cancer progression entails intricate, multi-level alterations in genome organization and expression. To gain insights into the modifications in chromatin's three-dimensional (3D) structure during breast cancer progression, we conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that while the fundamental properties of topologically associating domains (TADs) remain largely stable, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observed a restructuring of TAD-TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identified a previously unrecognized interchromosomal insertion event, wherein a locus on chromosome 8 housing the MYC oncogene becomes inserted into a highly active region on chromosome 10. This insertion event leads to the formation of de novo enhancer contacts and activation of the oncogene, illustrating how structural variants can interact with the 3D genome to drive oncogenic states. In summary, our findings provide evidence for the degradation of genome organization at multiple scales during breast cancer progression revealing the complex interplay between genomic structure and oncogenic processes.

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