Similar Datasets
Project description:Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes to silence existing cell-type-specific genes and activate pluripotency genes. ATP-dependent chromatin remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of recently identified Bromodomain-containing protein 9 (BRD9) and the associated non-canonical BRG1-associated factors (ncBAF) complex in reprogramming remains unknown. Here, we show that genetic or chemical inhibition of BRD9, as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, increase human somatic cell reprogramming efficiency and can replace KLF4 and c-MYC. We find that BRD9 is dispensable for human induced pluripotent stem cells under primed but not under naive conditions. Mechanistically, BRD9 inhibition downregulates fibroblast-related genes and decreases chromatin accessibility at somatic enhancers. BRD9 maintains the expression of transcriptional regulators MN1 and ZBTB38, both of which impede reprogramming. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers chromatin-based barriers to reprogramming.
| S-EPMC9768578 | biostudies-literature
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: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:BRD9-containing non-canonical BAF chromatin remodeling complex acts as a barrier to somatic cell reprogramming
| PRJNA678976 | ENA
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 (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: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: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 bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex. Degraders of BRD9 exhibit markedly enhanced potency compared to parental ligands (10- to 100-fold). Parallel study of degraders with divergent BRD9-binding chemotypes in models of acute myeloid leukemia resolves bromodomain polypharmacology in this emerging drug class. Together, these findings reveal the tractability of non-BET bromodomain containing proteins to chemical degradation, and highlight lead compound dBRD9 as a tool for the study of BRD9.
| S-EPMC5967236 | biostudies-literature