Similar Datasets
Project description:Brg1 and Brm function as alternative core enzymatic ATPases of SWI/SNF complex in vertebrates, with clear homologs in zebrafish. Brg1 (but not Brm) is required for early cleavage-stage transcription in mice, but where and how Brg1 or Brm impact chromatin in early embryos remains unexplored. Here, we utilize zebrafish embryos to provide the first simultaneous genome-wide profiling of Brg1 and Brm occupancy in any organism/cell type, alongside our profiling of open chromatin and RNA polymerase II. We reveal shared and unique loci for Brg1 and Brm, their shared occupancy of open chromatin and particular developmental promoters, and higher transcription at co-occupied genes. Interestingly, only Brg1 is strongly associated with active histone modifications. Strikingly, only Brm commonly occupies gene bodies, overlapping precisely with Pol II. Functional experiments involving Pol II elongation inhibition alongside bioinformatic analyses suggest that Brm travels with Pol II into gene bodies, primarily at short, very highly-transcribed genes with few introns. Taken together, our results support roles for Brg1 primarily at promoters and enhancers, and for Brm in association with Pol II in elongation through chromatin within gene bodies during genome-wide transcriptional activation
2024-05-24 | GSE175446 | GEO
Project description:Brg1 and Brm function as alternative core enzymatic ATPases of SWI/SNF complex in vertebrates, with clear homologs in zebrafish. Brg1 (but not Brm) is required for early cleavage-stage transcription in mice, but where and how Brg1 or Brm impact chromatin in early embryos remains unexplored. Here, we utilize zebrafish embryos to provide the first simultaneous genome-wide profiling of Brg1 and Brm occupancy in any organism/cell type, alongside our profiling of open chromatin and RNA polymerase II. We reveal shared and unique loci for Brg1 and Brm, their shared occupancy of open chromatin and particular developmental promoters, and higher transcription at co-occupied genes. Interestingly, only Brg1 is strongly associated with active histone modifications. Strikingly, only Brm commonly occupies gene bodies, overlapping precisely with Pol II. Functional experiments involving Pol II elongation inhibition alongside bioinformatic analyses suggest that Brm travels with Pol II into gene bodies, primarily at short, very highly-transcribed genes with few introns. Taken together, our results support roles for Brg1 primarily at promoters and enhancers, and for Brm in association with Pol II in elongation through chromatin within gene bodies during genome-wide transcriptional activation
2024-05-24 | GSE175444 | GEO
Project description:Distinctive roles for the chromatin remodeling ATPases Brg1 and Brm in early zebrafish embryos
| PRJNA732402 | ENA
Project description:Distinctive roles for the chromatin remodeling ATPases Brg1 and Brm in early zebrafish embryos [RNA-seq]
| PRJNA732405 | ENA
Project description:Distinctive roles for the chromatin remodeling ATPases Brg1 and Brm in early zebrafish embryos [ChIP-seq]
| PRJNA732404 | ENA
Project description:The mammalian SWI/SNF chromatin-remodeling complex is essential for the multiple changes in gene expression that occur during differentiation. However, the basis within the complex for specificity in effecting positive versus negative changes in gene expression has only begun to be elucidated. The catalytic core of the complex can be either of two closely related ATPases, BRM or BRG1, with the potential that the choice of alternative subunits is a key determinant of specificity. Short hairpin RNA-mediated depletion of the ATPases was used to explore their respective roles in the well characterized multistage process of osteoblast differentiation. The results reveal an unexpected role for BRM-specific complexes. Instead of impeding differentiation as was seen with BRG1 depletion, depletion of BRM caused accelerated progression to the differentiation phenotype. Multiple tissue-specific differentiation markers, including the tightly regulated late stage marker osteocalcin, become constitutively up-regulated in BRM-depleted cells. Chromatin immunoprecipitation analysis of the osteocalcin promoter as a model for the behavior of the complexes indicates that the promoter is a direct target of both BRM- and BRG1-containing complexes. BRG1 complexes, which are required for activation, are associated with the promoter well before induction, but the concurrent presence of BRM-specific complexes overrides their activation function. BRM-specific complexes are present only on the repressed promoter and are required for association of the co-repressor HDAC1. These findings reveal an unanticipated degree of specialization of function linked with the choice of ATPase and suggest a new paradigm for the roles of the alternative subunits during differentiation.
| S-EPMC2665061 | biostudies-literature
Project description:Endothelial-mesenchymal transition (EndMT) is considered one of the processes underlying tissue fibrosis by contributing to the pool of myofibroblasts. In the present study, we investigated the epigenetic mechanism whereby angiotensin II (Ang II) regulates EndMT to promote cardiac fibrosis focusing on the role of chromatin remodeling protein BRG1. BRG1 knockdown or inhibition attenuated Ang II-induced EndMT, as evidenced by down-regulation of CDH5, an endothelial marker, and up-regulation of COL1A2, a mesenchymal marker, in cultured vascular endothelial cells. On the one hand, BRG1 interacted with and was recruited by Sp1 to the SNAI2 (encoding SLUG) promoter to activate SNAI2 transcription in response to Ang II stimulation. Once activated, SLUG bound to the CDH5 promoter to repress CDH5 transcription. On the other hand, BRG1 interacted with and was recruited by SRF to the COL1A2 promoter to activate COL1A2 transcription. Mechanistically, BRG1 evicted histones from the target promoters to facilitate the bindings of Sp1 and SRF. Finally, endothelial conditional BRG1 knockout mice (CKO) exhibited a reduction in cardiac fibrosis, compared to the wild type (WT) littermates, in response to chronic Ang II infusion. In conclusion, our data demonstrate that BRG1 is a key transcriptional coordinator programming Ang II-induced EndMT to contribute to cardiac fibrosis.
| S-EPMC7368857 | biostudies-literature
Project description:There has been an increasing recognition that mitochondrial perturbations play a central role in human heart failure. Mitochondrial networks, whose function is to maintain the regulation of mitochondrial biogenesis, autophagy ('mitophagy') and mitochondrial fusion/fission, are new potential therapeutic targets. Yet our understanding of the molecular underpinning of these processes is just emerging. We recently identified a role of the SWI/SNF ATP-dependent chromatin remodeling complexes in the metabolic homeostasis of the adult cardiomyocyte using cardiomyocyte-specific and inducible deletion of the SWI/SNF ATPases BRG1 and BRM in adult mice (Brg1/Brm double mutant mice). To build upon these observations in early altered metabolism, the present study looks at the subsequent alterations in mitochondrial quality control mechanisms in the impaired adult cardiomyocyte. We identified that Brg1/Brm double-mutant mice exhibited increased mitochondrial biogenesis, increases in 'mitophagy', and alterations in mitochondrial fission and fusion that led to small, fragmented mitochondria. Mechanistically, increases in the autophagy and mitophagy-regulated proteins Beclin1 and Bnip3 were identified, paralleling changes seen in human heart failure. Evidence for perturbed cardiac mitochondrial dynamics included decreased mitochondria size, reduced numbers of mitochondria, and an altered expression of genes regulating fusion (Mfn1, Opa1) and fission (Drp1). We also identified cardiac protein amyloid accumulation (aggregated fibrils) during disease progression along with an increase in pre-amyloid oligomers and an upregulated unfolded protein response including increased GRP78, CHOP, and IRE-1 signaling. Together, these findings described a role for BRG1 and BRM in mitochondrial quality control, by regulating mitochondrial number, mitophagy, and mitochondrial dynamics not previously recognized in the adult cardiomyocyte. As critical to the pathogenesis of heart failure, epigenetic mechanisms like SWI/SNF chromatin remodeling seem more intimately linked to cardiac function and mitochondrial quality control mechanisms than previously realized.
| S-EPMC4860071 | biostudies-literature
Project description:Skeletal muscle regeneration is mediated by myoblasts that undergo epigenomic changes to establish the gene expression program of differentiated myofibers. mSWI/SNF chromatin remodeling enzymes coordinate with lineage-determining transcription factors to establish the epigenome of differentiated myofibers. Bromodomains bind to acetylated lysines on histone N-terminal tails and other proteins. The mutually exclusive ATPases of mSWI/SNF complexes, BRG1 and BRM, contain bromodomains with undefined functional importance in skeletal muscle differentiation. Pharmacological inhibition of mSWI/SNF bromodomain function using the small molecule PFI-3 reduced differentiation in cell culture and in vivo through decreased myogenic gene expression, while increasing cell cycle-related gene expression and the number of cells remaining in the cell cycle. Comparative gene expression analysis with data from myoblasts depleted of BRG1 or BRM showed that bromodomain function was required for a subset of BRG1- and BRM-dependent gene expression. Reduced binding of BRG1 and BRM after PFI-3 treatment showed that the bromodomain is required for stable chromatin binding at target gene promoters to alter gene expression. Our findings demonstrate that mSWI/SNF ATPase bromodomains permit stable binding of the mSWI/SNF ATPases to promoters required for cell cycle exit and establishment of muscle-specific gene expression.
| S-EPMC8373147 | biostudies-literature
Project description:Chromatin remodeling complexes play important roles in various DNA metabolism processes, including DNA damage repair. BRG1 is the core subunit of the SWI/SNF complex, which plays critical roles in cell cycle regulation, cell development, cell differentiation, and tumorigenesis. In the present study, we report that BRG1 depletion increased the percentage of apoptotic cells in etoposide-treated cells. Moreover, western blotting and immunofluorescence data showed that BRG1 depletion decreased H2AX phosphorylation and caused defective phosphorylated histone H2AX (γH2AX) clearance. Furthermore, we found that in both SW13 and U2OS cells, BRG1 expression could increase the sensitivity of genomic DNA to micrococcal nuclease (MNase) and facilitate chromatin relaxation around DNA damage sites. Thus, the results provide evidence that BRG1 plays an important role in early DNA damage repair by remodeling the chromatin structure near DNA damage sites.
| S-EPMC6282460 | biostudies-literature