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Dynamic BRG1 Recruitment During T Helper Differentiation And Activation Reveals Distal Regulatory Elements

ABSTRACT: We found binding of the remodeling protein BRG1 was programmed by lineage and activation signals. BRG1 binding was positively correlated with gene activity at protein-coding and miRNA genes. BRG1 binding was found at promoters and distal regions, including known and novel distal regulatory elements. Distal BRG1 binding correlated with expression, and novel distal sites possessed enhancer activity, suggesting a general role for BRG1 in long-distance gene regulation. Together, these findings suggest BRG1 interprets differentiation and activation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. Our findings indicate BRG1 binding is a useful marker for identifying cis-regulatory regions in protein-coding and miRNA genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE23719 | GEO | 2011/03/01

SECONDARY ACCESSION(S): PRJNA130875

REPOSITORIES: GEO

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Dynamic BRG1 Recruitment During T Helper Differentiation And Activation Reveals Distal Regulatory Elements

Project description:We found binding of the remodeling protein BRG1 was programmed by lineage and activation signals. BRG1 binding was positively correlated with gene activity at protein-coding and miRNA genes. BRG1 binding was found at promoters and distal regions, including known and novel distal regulatory elements. Distal BRG1 binding correlated with expression, and novel distal sites possessed enhancer activity, suggesting a general role for BRG1 in long-distance gene regulation. Together, these findings suggest BRG1 interprets differentiation and activation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. Our findings indicate BRG1 binding is a useful marker for identifying cis-regulatory regions in protein-coding and miRNA genes. Compare BRG1 binding in T helper subsets genome wide; Naïve, resting Th1, resting Th2, Stimulated Th1, Stimulated Th2, Stimulated Th17, compared to input DNA as negative control

2011-03-01 | E-GEOD-23719 | biostudies-arrayexpress

Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism

Project description:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in SCCOHT cell lines +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon AP-1 activity.

2021-01-15 | PXD014134 | Pride

Sequencing of Coding and Non-coding Regions in Primary Breast Cancers and Patient-matched Controls

Project description:<p>Genomic analysis of tumor samples has led to the identification of hundreds of cancer genes based on the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here, we performed deep sequencing in 360 primary breast cancers and developed computational methods to identify significantly mutated promoters. Clear signals were found in the promoters of four genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbors a mutational hotspot in its promoter that leads to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that alter protein binding to the promoter and impact expression levels. Overall, our study shows that recurrent mutations in or near gene promoters in cancers have functional consequences. Power analyses indicate that more such genes remain to be discovered through deep sequencing of adequately sized patient cohorts. </p>

| phs001250 | dbGaP

Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism [ChIP-seq]

Project description:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that the BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.

2020-12-30 | GSE151018 | GEO

Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism [ATAC-seq]

Project description:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that the BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.

2020-12-30 | GSE151014 | GEO

Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism [CUT&RUN]

Project description:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that the BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.

2021-01-04 | GSE162626 | GEO

Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism [RNA-seq]

Project description:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that the BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.

2020-12-30 | GSE151025 | GEO

Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism [AFOS RNA-seq]

Project description:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that the BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.

2020-12-30 | GSE151024 | GEO

Regulation of nucleosome landscape and transcription factor binding at enhancers by BRG1

Project description:Enhancers of transcription activate transcription via binding of sequence-specific transcription factors to their target sites in chromatin. In this report, we identify GATA1-bound enhancers genome-wide and find a global reorganization of the nucleosomes at these enhancers during differentiation of hematopoietic stem cells (HSCs) to erythrocytes. We show that the catalytic subunit BRG1 of BAF complexes localizes to these enhancers during differentiation and generates a longer nucleosome repeat length surrounding the GATA1 sites by shifting the flanking nucleosomes away. Intriguing, we find that the nucleosome shifting specifically facilitates binding of TAL1 but not GATA1, which subsequently activates transcription of target genes. Human hematopoietic stem cells (referred as CD34+ cells) were differentiated into erythroid lineage expressing the cell surface marker CD36 (referred as CD36+ cells). To study the function of ATP-dependent chromatin remodeling BAF complexes in the establishment of erythroid specific enhancers during differentiation, we mapped the genome-wide binding sites of GATA1 and TAL1, the key transcription regulators of erythroid differentiation, in CD36+ cells, then determined the genomic positions of the catalytic subunit BRG1 of the BAF complexes and the nucleosome landscapes, by ChIP-Seq and Mnase-Seq, respectively, for both HSCs and the differentiated cells. We compared changes in nucleosome landscapes with BRG1 binding at GATA1 and TAL1 binding sites and found that BRG1 binding is correlated with nucleosome shifting away from the binding sites, which is critical for TAL1 binding. To confirm that BRG1 is responsible for the nucleosome shift, we knocked down BRG1 in CD36+ cells and analyzed the nucleosome changes in the knockdown cells. The data indicated that inhibition of BRG1 caused a nucleosome shift towards the GATA1 or TAL1 sites, indicating that BRG1 is indeed responsible for the observed nucleosome shift.

2011-07-01 | E-GEOD-26501 | biostudies-arrayexpress

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

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