Loss of PBAF Promotes Effector Differentiation and Limits CD8+ T Cell Exhaustion in Chronic Viral Infection and Cancer [multiomics]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE222346 | GEO | 2023/06/22
REPOSITORIES: GEO
Similar Datasets
Project description:Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the putative tumor suppressor proteins PBRM1 (BAF180) and ARID2 (BAF200) that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, ARID2 and histone mark ChIP-seq, and ATAC-seq data to show that PBAF acts to enhance or repress gene expression depending on the genomic context. At baseline, ARID2 binds to areas of open chromatin at both active enhancers and promoters. Depletion of PBRM1 leads to attenuated and redistributed ARID2 chromatin binding that correlates significantly with gene expression changes. At enhancers, ARID2 binding loss leads to diminishment of the histone mark H3K4me1 and gene downregulation. Alternatively, at a subset of promoters, ARID2 binding loss derepresses gene expression. Interestingly, ARID2, which remains bound to other PBAF subunits after loss of PBRM1, is essential for many of the pro-tumorigenic transcriptional changes observed after loss of PBRM1, whereas other core SWI/SNF components are dispensable. Upon loss of PBRM1, ARID2 positively regulates cancer-related genes and pathways, including the cancer stem cell marker ALDH1A1 and EGF signaling, to stimulate tumor cell growth. Therefore, ARID2 is crucial for maintaining the transformed state of PBRM1-deficient ccRCC cells. In total, this study suggests a novel mechanism of transcriptional control by PBRM1, whereby its loss alters the chromatin distribution of the residual PBAF complex leading to altered transcription that promotes tumorigenesis.
2018-08-14 | GSE102806 | GEO
Project description:Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the putative tumor suppressor proteins PBRM1 (BAF180) and ARID2 (BAF200) that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, ARID2 and histone mark ChIP-seq, and ATAC-seq data to show that PBAF acts to enhance or repress gene expression depending on the genomic context. At baseline, ARID2 binds to areas of open chromatin at both active enhancers and promoters. Depletion of PBRM1 leads to attenuated and redistributed ARID2 chromatin binding that correlates significantly with gene expression changes. At enhancers, ARID2 binding loss leads to diminishment of the histone mark H3K4me1 and gene downregulation. Alternatively, at a subset of promoters, ARID2 binding loss derepresses gene expression. Interestingly, ARID2, which remains bound to other PBAF subunits after loss of PBRM1, is essential for many of the pro-tumorigenic transcriptional changes observed after loss of PBRM1, whereas other core SWI/SNF components are dispensable. Upon loss of PBRM1, ARID2 positively regulates cancer-related genes and pathways, including the cancer stem cell marker ALDH1A1 and EGF signaling, to stimulate tumor cell growth. Therefore, ARID2 is crucial for maintaining the transformed state of PBRM1-deficient ccRCC cells. In total, this study suggests a novel mechanism of transcriptional control by PBRM1, whereby its loss alters the chromatin distribution of the residual PBAF complex leading to altered transcription that promotes tumorigenesis.
2018-08-14 | GSE102805 | GEO
Project description:Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the putative tumor suppressor proteins PBRM1 (BAF180) and ARID2 (BAF200) that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, ARID2 and histone mark ChIP-seq, and ATAC-seq data to show that PBAF acts to enhance or repress gene expression depending on the genomic context. At baseline, ARID2 binds to areas of open chromatin at both active enhancers and promoters. Depletion of PBRM1 leads to attenuated and redistributed ARID2 chromatin binding that correlates significantly with gene expression changes. At enhancers, ARID2 binding loss leads to diminishment of the histone mark H3K4me1 and gene downregulation. Alternatively, at a subset of promoters, ARID2 binding loss derepresses gene expression. Interestingly, ARID2, which remains bound to other PBAF subunits after loss of PBRM1, is essential for many of the pro-tumorigenic transcriptional changes observed after loss of PBRM1, whereas other core SWI/SNF components are dispensable. Upon loss of PBRM1, ARID2 positively regulates cancer-related genes and pathways, including the cancer stem cell marker ALDH1A1 and EGF signaling, to stimulate tumor cell growth. Therefore, ARID2 is crucial for maintaining the transformed state of PBRM1-deficient ccRCC cells. In total, this study suggests a novel mechanism of transcriptional control by PBRM1, whereby its loss alters the chromatin distribution of the residual PBAF complex leading to altered transcription that promotes tumorigenesis.
2018-08-14 | GSE102804 | GEO
Project description:Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the putative tumor suppressor proteins PBRM1 (BAF180) and ARID2 (BAF200) that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, ARID2 and histone mark ChIP-seq, and ATAC-seq data to show that PBAF acts to enhance or repress gene expression depending on the genomic context. At baseline, ARID2 binds to areas of open chromatin at both active enhancers and promoters. Depletion of PBRM1 leads to attenuated and redistributed ARID2 chromatin binding that correlates significantly with gene expression changes. At enhancers, ARID2 binding loss leads to diminishment of the histone mark H3K4me1 and gene downregulation. Alternatively, at a subset of promoters, ARID2 binding loss derepresses gene expression. Interestingly, ARID2, which remains bound to other PBAF subunits after loss of PBRM1, is essential for many of the pro-tumorigenic transcriptional changes observed after loss of PBRM1, whereas other core SWI/SNF components are dispensable. Upon loss of PBRM1, ARID2 positively regulates cancer-related genes and pathways, including the cancer stem cell marker ALDH1A1 and EGF signaling, to stimulate tumor cell growth. Therefore, ARID2 is crucial for maintaining the transformed state of PBRM1-deficient ccRCC cells. In total, this study suggests a novel mechanism of transcriptional control by PBRM1, whereby its loss alters the chromatin distribution of the residual PBAF complex leading to altered transcription that promotes tumorigenesis.
2018-08-14 | GSE102803 | GEO
Project description:Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the putative tumor suppressor proteins PBRM1 (BAF180) and ARID2 (BAF200) that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, ARID2 and histone mark ChIP-seq, and ATAC-seq data to show that PBAF acts to enhance or repress gene expression depending on the genomic context. At baseline, ARID2 binds to areas of open chromatin at both active enhancers and promoters. Depletion of PBRM1 leads to attenuated and redistributed ARID2 chromatin binding that correlates significantly with gene expression changes. At enhancers, ARID2 binding loss leads to diminishment of the histone mark H3K4me1 and gene downregulation. Alternatively, at a subset of promoters, ARID2 binding loss derepresses gene expression. Interestingly, ARID2, which remains bound to other PBAF subunits after loss of PBRM1, is essential for many of the pro-tumorigenic transcriptional changes observed after loss of PBRM1, whereas other core SWI/SNF components are dispensable. Upon loss of PBRM1, ARID2 positively regulates cancer-related genes and pathways, including the cancer stem cell marker ALDH1A1 and EGF signaling, to stimulate tumor cell growth. Therefore, ARID2 is crucial for maintaining the transformed state of PBRM1-deficient ccRCC cells. In total, this study suggests a novel mechanism of transcriptional control by PBRM1, whereby its loss alters the chromatin distribution of the residual PBAF complex leading to altered transcription that promotes tumorigenesis.
2018-08-14 | GSE102656 | GEO
Project description:PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler. The inactivation of PBRM1 is the second most frequent mutational event in kidney tumorigenesis. Here we show that in VHL-deficient ccRCC tumors, PBRM1 loss results in an altered PBAF complex that retains the association between SMARCA4 and ARID2 but disengages BRD7 from SMARCA4. The PBRM1-deficient PBAF complexes redistribute from promoter proxy regions to distal enhancer regions. The ATPase function of SMARCA4 enhances the recruitment of nuclear factor RELA to aberrant sites and promotes NF-κB activity. Proteasome inhibitor bortezomib reverses NF-κB activation by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.
2023-02-13 | GSE152734 | GEO
Project description:ARID2 is an essential subunit of the SWI/SNF PBAF chromatin remodeler and is highly mutate in melanoma. To elucidate the role of ARID2 in melanoma biology and chromatin structure we utilized CRISPR Cas9 methodology to generate isogenic ARID2 WT and KO melanoma clonal cell lines. We further map the genomic localization of several SWI/SNF subunits, open and repressed chromatin markers, and multiple transcription factors to characterize how loss of the PBAF subcomplex alters chromatin accessibility and the melanoma transcription factor network. Finally, we characterized the transcriptional changes produced by PBAF depletion.
2022-04-05 | GSE172383 | GEO
Project description:Multimeric SWI/SNF chromatin remodelers assemble in distinct conformations, with individual functions difficult to dissect. Importantly, mutations in specific SWI/SNF genes are enriched in distinct cancers, as the PBAF-specific component ARID2 in melanoma. Through comprehensive epigenomic profiling of SWI/SNF complexes and their associated chromatin states in melanoma and melanocytes, we found that a subset of PBAF-exclusive regions unexpectedly coexists with PRC2 and repressed chromatin. Time-resolved approaches revealed that PBAF regions are generally less sensitive to ATPase-mediated remodeling compared to BAF sites. Notably, PBAF/PRC2-bound loci are enriched for REST, a transcription factor that represses neuronal genes. In turn, absence of ARID2 and consequent PBAF loss hinders REST ability to bind and inactivate its targets, leading to upregulation of neuronal and synaptic transcripts, a gene signature also associated with ARID2 mutations in melanoma patients. In sum, we demonstrate a unique role for PBAF in generating accessibility for a silencing transcription factor at repressed chromatin.
2024-10-01 | GSE272705 | GEO
Project description:Multimeric SWI/SNF chromatin remodelers assemble in distinct conformations, with individual functions difficult to dissect. Importantly, mutations in specific SWI/SNF genes are enriched in distinct cancers, as the PBAF-specific component ARID2 in melanoma. Through comprehensive epigenomic profiling of SWI/SNF complexes and their associated chromatin states in melanoma and melanocytes, we found that a subset of PBAF-exclusive regions unexpectedly coexists with PRC2 and repressed chromatin. Time-resolved approaches revealed that PBAF regions are generally less sensitive to ATPase-mediated remodeling compared to BAF sites. Notably, PBAF/PRC2-bound loci are enriched for REST, a transcription factor that represses neuronal genes. In turn, absence of ARID2 and consequent PBAF loss hinders REST ability to bind and inactivate its targets, leading to upregulation of neuronal and synaptic transcripts, a gene signature also associated with ARID2 mutations in melanoma patients. In sum, we demonstrate a unique role for PBAF in generating accessibility for a silencing transcription factor at repressed chromatin.
2024-10-01 | GSE275420 | GEO
Project description:ARID2 is an essential subunit of the SWI/SNF PBAF chromatin remodeler and is highly mutate in melanoma. To elucidate the role of ARID2 in melanoma biology and chromatin structure we utilized CRISPR Cas9 methodology to generate isogenic ARID2 WT and KO melanoma clonal cell lines. We further map the genomic localization of several SWI/SNF subunits, open and repressed chromatin markers, and multiple transcription factors to characterize how loss of the PBAF subcomplex alters chromatin accessibility and the melanoma transcription factor network. Finally, we characterized the transcriptional changes produced by PBAF depletion.
2022-04-05 | GSE172384 | GEO