A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naïve pluripotency in mouse embryonic stem cells
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ABSTRACT:
PROVIDER: PRJNA436371 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6792750.fastq.gz | Fastqsanger.gz | |||
| SRR6792731.fastq.gz | Fastqsanger.gz | |||
| SRR6792751.fastq.gz | Fastqsanger.gz | |||
| SRR6792742.fastq.gz | Fastqsanger.gz | |||
| SRR6792752.fastq.gz | Fastqsanger.gz |
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Project description:The mammalian BRG1-associated factors (BAF) complex is a multi-subunit chromatin remodeling complex that is an important component of the embryonic stem cell (ESC) transcriptional regulatory network. However, the role of individual subunits in BAF complex targeting and function needs to be elucidated. Here, we find that the Bromodomain containing protein 9 (BRD9) defines a smaller, non-canonical BAF complex in mouse ESCs that is distinct from the canonical embryonic stem cell BAF (esBAF) and the polybromo-associated BAF (PBAF) complexes. This BRD9-containing BAF complex, or BBAF complex, uniquely incorporates the BRD4-interacting chromatin remodeling associated protein-like (BICRAL) or its paralog BICRA and lacks several esBAF subunits including BAF47, ARID1A and BAF57. We demonstrate that BBAF and esBAF complexes are targeted to different features of the genome and are co-bound with different sets of pluripotency transcription factors. Specifically, BBAF complexes co-localize with key regulators of naïve pluripotency, KLF4 and Sp5, on the genome. Consistent with this, we provide evidence that BBAF’s specific function is to regulate the transcription of genes involved in the maintenance of naïve pluripotency, including Nanog and Prdm14. Additionally, we show that BRD9 is displaced from chromatin by the selective BRD9 bromodomain inhibitor, I-BRD9, and that this leads to changes in target gene expression. Together, our results provide evidence for the identification of a new BAF complex, and demonstrate functionally specific roles for BAF complex assemblies in maintaining the transcriptional network of pluripotency.
2018-10-18 | PXD010670 | Pride
Project description:The mammalian BRG1-associated factors (BAF) complex is a multi-subunit chromatin remodeling complex that is an important component of the embryonic stem cell (ESC) transcriptional regulatory network. However, the role of individual subunits in BAF complex targeting and function needs to be elucidated. Here, we find that the Bromodomain containing protein 9 (BRD9) and Glioma tumor suppressor candidate region gene 1 (GLTSCR1; also known as BICRA) or its paralog GLTSCR1-like (also known as BICRAL) define a smaller, non-canonical BAF complex (GBAF for GLTSCR1/1L-containing BAF complex) in mouse ESCs that is distinct from the canonical embryonic stem cell BAF (esBAF) and the polybromo-associated BAF (PBAF) complexes. GBAF lacks several esBAF subunits, including BAF47, BAF57 and ARID1A. We demonstrate that GBAF and esBAF complexes are targeted to different features of the genome and are co-bound with different sets of pluripotency transcription factors. Specifically, GBAF complexes co-localize with key regulators of naïve pluripotency, KLF4 and Sp5, on the genome. Consistent with this, we provide evidence that GBAF's specific function is to regulate the transcription of genes involved in the maintenance of naïve pluripotency, including Nanog and Prdm14. Additionally, we show that BRD9 is displaced from chromatin by the selective BRD9 bromodomain inhibitor, I-BRD9, and that this leads to changes in target gene expression. The function of the GBAF complex in ESCs is highly correlated with the function of BRD4, consistent with an association between GBAF complexes and BRD4. We find that GBAF complexes are directly recruited to chromatin by BRD4 in a bromodomain-dependent fashion and we identify a set of I-BRD9- and JQ1-sensitive BRD9 binding sites that determine the functional similarity between these epigenetic regulators. Together, our results demonstrate functionally specific roles for BAF complex assemblies in maintaining the transcriptional network of pluripotency, highlighting the biological importance of complex heterogeneity.
2018-10-19 | GSE111264 | GEO
Project description:Epigenetic reprogramming requires extensive remodeling of chromatin landscapes to silence gene expression programs which sustain cell identity. ATP-dependent chromatin-remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of Bromodomain containing protein 9 (BRD9) and the associated ncBAF (non-canonical BRG1-associated factors) complex in somatic cell reprogramming remains unknown. Here, we show that inhibition and acute degradation of BRD9 increases the efficiency by which induced pluripotent stem cells (iPSCs) can be generated from human fibroblasts. Genetic suppression of BRD9 as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, phenocopied this effect. CRISRP/Cas9-mediated knockout of BRD9 demonstrated that it is dispensable for establishment and maintenance of human pluripotency. Mechanistically, BRD9 inhibition facilitates reprogramming by downregulating somatic cell type-specific genes and decreasing chromatin accessibility at somatic enhancers. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers barriers to reprogramming.
2021-06-15 | GSE161637 | GEO
Project description:Epigenetic reprogramming requires extensive remodeling of chromatin landscapes to silence gene expression programs which sustain cell identity. ATP-dependent chromatin-remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of Bromodomain containing protein 9 (BRD9) and the associated ncBAF (non-canonical BRG1-associated factors) complex in somatic cell reprogramming remains unknown. Here, we show that inhibition and acute degradation of BRD9 increases the efficiency by which induced pluripotent stem cells (iPSCs) can be generated from human fibroblasts. Genetic suppression of BRD9 as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, phenocopied this effect. CRISRP/Cas9-mediated knockout of BRD9 demonstrated that it is dispensable for establishment and maintenance of human pluripotency. Mechanistically, BRD9 inhibition facilitates reprogramming by downregulating somatic cell type-specific genes and decreasing chromatin accessibility at somatic enhancers. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers barriers to reprogramming.
2021-06-15 | GSE161639 | GEO
Project description:The role of individual subunits in the targeting and function of the mammalian BRG1-associated factors (BAF) complex in embryonic stem cell (ESC) pluripotency maintenance has not yet been elucidated. Here we find that the Bromodomain containing protein 9 (BRD9) and Glioma tumor suppressor candidate region gene 1 (GLTSCR1) or its paralog GLTSCR1-like (GLTSCR1L) define a smaller, non-canonical BAF complex (GBAF complex) in mouse ESCs that is distinct from the canonical ESC BAF complex (esBAF). GBAF and esBAF complexes are targeted to different genomic features, with GBAF co-localizing with key regulators of naive pluripotency, which is consistent with its specific function in maintaining naive pluripotency gene expression. BRD9 interacts with BRD4 in a bromodomain-dependent fashion, which leads to the recruitment of GBAF complexes to chromatin, explaining the functional similarity between these epigenetic regulators. Together, our results highlight the biological importance of BAF complex heterogeneity in maintaining the transcriptional network of pluripotency.
| S-EPMC6277444 | biostudies-literature
Project description:BRD9-containing non-canonical BAF chromatin remodeling complex acts as a barrier to somatic cell reprogramming
| PRJNA678976 | ENA
Project description:SF3B1 is the most commonly mutated RNA splicing factor in cancer, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here, we integrated pan-cancer RNA sequencing to identify mutant SF3B1-dependent aberrant splicing with a positive enrichment CRISPR screen to prioritize splicing alterations that functionally promote tumorigenesis. We identify that diverse, recurrent SF3B1 mutations converge on repression of BRD9, a core component of the recently described non-canonical BAF (ncBAF) complex. Mutant SF3B1 recognizes an aberrant deep intronic branchpoint within BRD9, thereby inducing inclusion of an endogenous retrovirus-derived poison exon and BRD9 mRNA degradation. BRD9 depletion causes loss of ncBAF at CTCF-bound loci and promotes melanomagenesis. We demonstrate that BRD9 is a potent tumor suppressor in uveal melanoma, such that correcting BRD9 mis-splicing in SF3B1-mutant cell lines and patient-derived melanoma xenografts with antisense oligonucleotides (ASOs) or by directly targeting its poison exon with CRISPR-directed mutagenesis profoundly suppresses tumor growth. Our results implicate disruption of ncBAF in the diverse malignancies characterized by SF3B1 mutations, identify a single aberrant splicing event which functionally contributes to the pathogenesis of SF3B1-mutant cancers, and suggest a mechanism-based therapeutic for these malignancies.
2019-06-19 | GSE124720 | GEO
Project description:BRD9-containing non-canonical BAF chromatin remodeling complex acts as a barrier to somatic cell reprogramming (ATAC-Seq)
| PRJNA678984 | ENA
Project description:BRD9-containing non-canonical BAF chromatin remodeling complex acts as a barrier to somatic cell reprogramming (RNA-Seq)
| PRJNA678985 | ENA
Project description:H3K27ac is known to associate with regulatory active enhancers, but it’s exact role in enhancer function remains elusive. Using mass spectrometry-based interaction proteomics, we identified the Super Elongation Complex (SEC) and GBAF, a non-canonical GLTSCR1L- and BRD9-containing SWI/SNF chromatin remodeling complex, to be major interactors of H3K27ac. Our interaction proteomics analysis refined the composition of GBAF by adding BCL7A/B/C as a new subunit. We further characterized the conserved GLTSCR1/1L-contained “GiBAF”-domain, which we found to be responsible for GBAF complex formation and nuclear localization. Inhibition of the bromodomain of BRD9 revealed interaction between GLTSCR1L and BRD9 to be H3K27ac dependent and led to GLTSCR1L dislocation from its preferred binding sites at H3K27ac-associated enhancers. GLTSCR1L disassociation from chromatin resulted in a genome-wide downregulation of enhancer transcription. Our results indicate that GBAF is an enhancer-associated chromatin remodeller important for the correct transcriptional and regulatory activity of enhancers.
2018-10-17 | GSE121351 | GEO