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SWI/SNF is a gatekeeper of chromatin access at enhancer networks controlling triple-negative breats cancer progression [ATAC-seq]

ABSTRACT: Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with high metastatic potential, limited treatment options, and low patient survival rates. By combining proteomics and genomics approaches, we identify an oncogenic transcriptional network in TNBC involving the glucocorticoid receptor (GR), GATA6, the key oncoprotein MYC, and AP-1 transcription factors. Although these transcription factors share cis-regulatory regions, they control largely distinct oncogenic pathways. We demonstrate that SWI/SNF chromatin remodeling complex is a common gatekeeper of chromatin access for these transcription factors, and that inhibition of SWI/SNF-mediated chromatin remodeling decommissions the distinct enhancer repertoires and target gene programs controlled by these transcription factors. Consistently, SWI/SNF inhibition blocks cancer cell proliferation, chemoresistance, and invasion both in vitro and in vivo. Thus, we propose that several key oncogenic pathways in TNBC depend on SWI/SNF-mediated chromatin remodeling, making this disease vulnerable to SWI/SNF inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261986 | GEO | 2025/08/27

REPOSITORIES: GEO

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SWI/SNF is a gatekeeper of chromatin access at enhancer networks controlling triple-negative breast cancer progression

Project description:Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with high metastatic potential, limited treatment options and low patient survival rates. By combining functional proteomics and genomics approaches, we identify an oncogenic transcriptional network in mesenchymal and invasive TNBC involving the glucocorticoid receptor (GR), GATA6, MYC and AP-1 transcription factors. Although these transcription factors bind extensively to shared enhancers, they utilize different enhancer repertoires from this shared enhancer pool to drive distinct downstream oncogenic pathways. We demonstrate that the SWI/SNF chromatin remodeling complex is a common gatekeeper of chromatin access for these transcription factors, and SWI/SNF inhibition decommissions the distinct enhancer networks and pro-tumorigenic gene programs they control. Consistently, SWI/SNF inhibition blocks growth, glucocorticoid-induced chemoresistance and invasion/metastasis. Thus, we propose that SWI/SNF-mediated chromatin remodeling drives multiple hallmarks of TNBC progression, positioning SWI/SNF as a promising therapeutic target in this disease.

2025-08-27 | PXD050921 | Pride

SWI/SNF is a gatekeeper of chromatin access at enhancer networks controlling triple-negative breast cancer progression [RNA-Seq]

Project description:Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with high metastatic potential, limited treatment options, and low patient survival rates. By combining proteomics and genomics approaches, we identify an oncogenic transcriptional network in TNBC involving the glucocorticoid receptor (GR), GATA6, the key oncoprotein MYC, and AP-1 transcription factors. Although these transcription factors share cis-regulatory regions, they control largely distinct oncogenic pathways. We demonstrate that SWI/SNF chromatin remodeling complex is a common gatekeeper of chromatin access for these transcription factors, and that inhibition of SWI/SNF-mediated chromatin remodeling decommissions the distinct enhancer repertoires and target gene programs controlled by these transcription factors. Consistently, SWI/SNF inhibition blocks cancer cell proliferation, chemoresistance, and invasion both in vitro and in vivo. Thus, we propose that several key oncogenic pathways in TNBC depend on SWI/SNF-mediated chromatin remodeling, making this disease vulnerable to SWI/SNF inhibitors.

2025-08-27 | GSE261989 | GEO

SWI/SNF is a gatekeeper of chromatin access at enhancer networks controlling triple-negative breast cancer progression [ChIP-Seq]

Project description:Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with high metastatic potential, limited treatment options, and low patient survival rates. By combining proteomics and genomics approaches, we identify an oncogenic transcriptional network in TNBC involving the glucocorticoid receptor (GR), GATA6, the key oncoprotein MYC, and AP-1 transcription factors. Although these transcription factors share cis-regulatory regions, they control largely distinct oncogenic pathways. We demonstrate that SWI/SNF chromatin remodeling complex is a common gatekeeper of chromatin access for these transcription factors, and that inhibition of SWI/SNF-mediated chromatin remodeling decommissions the distinct enhancer repertoires and target gene programs controlled by these transcription factors. Consistently, SWI/SNF inhibition blocks cancer cell proliferation, chemoresistance, and invasion both in vitro and in vivo. Thus, we propose that several key oncogenic pathways in TNBC depend on SWI/SNF-mediated chromatin remodeling, making this disease vulnerable to SWI/SNF inhibitors.

2025-08-27 | GSE261988 | GEO

Genome-wide profile of the SWI/SNF chromatin remodeling complex

Project description:A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5M-bM-^@M-^Y ends, RNA Polymerases II and III and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins and DNA replication origins). To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members as well as with cellular constituents such as nuclear matrix proteins, key transcription factors and centromere components implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated. ChIP-Seq analysis of the SWI/SNF subunits Ini1, Brg1, BAF155 and BAF170 in HeLa S3 cells

2011-01-10 | E-GEOD-24397 | biostudies-arrayexpress

Lamin binding profiles in the ENCODE regions

Project description:A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5’ ends, RNA Polymerases II and III and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins and DNA replication origins). To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members as well as with cellular constituents such as nuclear matrix proteins, key transcription factors and centromere components implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated. ChIP-chip analysis of lamin A/C and lamin B in HeLa S3 cells

2011-01-10 | E-GEOD-24382 | biostudies-arrayexpress

Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodeling complex

Project description:Tissue-specific transcription factors initiate differentiation toward a specialized cell type by inducing transcription-permissive chromatin modifications at target gene promoters, through the recruitment of the SWI/SNF chromatin-remodeling complex (1, 2). The molecular mechanism that regulates the chromatin re-distribution of SWI/SNF in response to differentiation signals is currently unknown. Here we show that the muscle determination factor MyoD and the SWI/SNF structural sub-unit, BAF60c (SMARCD3), form a complex on the regulatory elements of MyoD-target genes in undifferentiated myoblasts, prior to the activation of gene expression. MyoD-BAF60c complex is devoid of the ATP-dependent enzymatic sub-units Brg1 and Brm, is required for stable MyoD binding to Ebox sequences, and marks the chromatin for signal-dependent recruitment of the SWI/SNF core complex to muscle loci. BAF60c phosphorylation on a conserved threonine by differentiation-activated p38 signalling promotes the incorporation of MyoD-BAF60c into a Brg1-based SWI/SNF complex, which is competent to remodel the chromatin and activates transcription of MyoD-target genes. Our data support an unprecedented two-step model, by which pre-assembled BAF60c-MyoD complex directs the SWI/SNF complex chromatin re-distribution to muscle loci in response to differentiation cues. Differentiation of C2C12 cells individually interfered for BRG1, BAF60B, BAF60C

2011-03-07 | E-GEOD-24573 | biostudies-arrayexpress

The hematopoietic master transcription factor PU.1 requires its interaction with the SWI/SNF remodeler to access chromatin de novo

Project description:PU.1 is a prototype master transcription factor (TF) of hematopoietic cell differentiation with diverse roles in different lineages. Analysis of its genome-wide binding pattern across PU.1 expressing cell types revealed manifold cell type-specific binding patterns. They are not consistent with the epigenetic and chromatin constraints to PU.1 binding observed in vitro, suggesting that PU.1 requires auxiliary factors to access DNA in vivo. Using a model of transient mRNA expression we show that PU.1 induction leads to the extensive remodeling of chromatin, redistribution of partner transcription factors and rapid initiation of a myeloid gene expression program in heterologous cell types. By probing PU.1 mutants for defects in chromatin access and screening for PU.1 proximal proteins in vivo, we found that its N-terminal acidic domain was required for the recruitment of SWI/SNF remodeling complexes, de novo chromatin access and stable binding as well as the redistribution of partner TFs.

2019-11-20 | PXD013167 | Pride

Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation [array]

Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs In order to understanding the transcription regulation network downstream of Brg1 in murine AML, we performed microarray in murine MLL-AF9/NrasG12D cell line under the condition that Brg1 was suppressed by three independent shRNAs for 96h.

2013-12-02 | E-GEOD-52231 | biostudies-arrayexpress

Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation (RNA-seq)

Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs To profile the basal transcription level, we performed NSR and PolyA+ (illumine TruSeq) in a murine AML RN2 cell lines. To define the rapid downregulated genes in response to JQ1, BET bromodomian inhibitor, in RN2 cell, we performed RNA-seq in RN2 exposing to 250nM JQ1 for 48h time course.

2013-12-02 | E-GEOD-52623 | biostudies-arrayexpress

Transcription profiling of fission yeast strains identifies widespread requirement for SWI/SNF and RSC on transcription

Project description:SWI/SNF chromatin remodeling complexes play critical roles in transcription and other chromatin-related processes. The analysis of the two members of this class in Saccharomyces cerevisiae, SWI/SNF and RSC, has heavily contributed to our understanding of these complexes. To understand the in vivo functions of SWI/SNF and RSC in an evolutionarily distant organism, we have characterized these complexes in Schizosaccharomyces pombe. While core components are conserved between the two yeasts, the compositions of S. pombe SWI/SNF and RSC differ from their S. cerevisiae counterparts and in some ways are more similar to metazoan complexes. Furthermore, several of the conserved proteins, including actin-like proteins, are strikingly different between the two yeasts with respect to their requirement for viability. Finally, phenotypic and microarray analyses identified widespread requirements for SWI/SNF and RSC on transcription including strong evidence that SWI/SNF directly represses iron transport genes.

2008-06-13 | E-MTAB-31 | biostudies-arrayexpress

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