Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA254022 | ENA |
REPOSITORIES: ENA
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Project description:The current studies show that JMJD1A is phosphorylated at S265 by protein kinase A (PKA), and this is pivotal to activate expression of the b1-adrenergic receptor gene (Adrb1) and downstream targets including Ucp1. Phosphorylation of JMJD1A increases its interaction with the SWI/SNF nucleosome remodeling complex and DNA-bound PPARg. This complex conferred b-adrenergic-induced JMJD1A recruitment to target sites throughout the genome. Phospho-JMJD1A also facilitated long-range chromatin looping to recruit PPARg-bound distal-enhancers, SWI/SNF, and RNA polymerase close to the Adrb1 locus to activate transcription. Mutation of the PKA-phosphorylation site on JMJD1A abolished interactions with SWI/SNF without affecting demethylase activity suggesting the two functions are independent of each other. Our results show that JMJD1A demethylase is also a signal-sensing scaffold that regulates cAMP-responsive transcription via interactions with SWI/SNF and hormone stimulated higher-order chromatin conformational changes. There are 3 samples analyzed. No duplication from each sample. Isoproterenol stimulation at 0hr is used as the relative to fold change in manuscript.
2015-04-15 | E-GEOD-58936 | biostudies-arrayexpress
Project description:The current studies show that JMJD1A is phosphorylated at S265 by protein kinase A (PKA), and this is pivotal to activate expression of the b1-adrenergic receptor gene (Adrb1) and downstream targets including Ucp1. Phosphorylation of JMJD1A increases its interaction with the SWI/SNF nucleosome remodeling complex and DNA-bound PPARg. This complex conferred b-adrenergic-induced JMJD1A recruitment to target sites throughout the genome. Phospho-JMJD1A also facilitated long-range chromatin looping to recruit PPARg-bound distal-enhancers, SWI/SNF, and RNA polymerase close to the Adrb1 locus to activate transcription. Mutation of the PKA-phosphorylation site on JMJD1A abolished interactions with SWI/SNF without affecting demethylase activity suggesting the two functions are independent of each other. Our results show that JMJD1A demethylase is also a signal-sensing scaffold that regulates cAMP-responsive transcription via interactions with SWI/SNF and hormone stimulated higher-order chromatin conformational changes.
2015-04-15 | GSE58936 | GEO
Project description:The SWI/SNF (or BAF) complex is an essential chromatin remodeler that regulates DNA accessibility at developmental genes and enhancers. SWI/SNF subunits are among the most frequently mutated genes in cancer and neurodevelopmental disorders. These mutations are often heterozygous loss-of-function alleles, indicating a dosage-sensitive role for SWI/SNF subunits in chromatin regulation. However, the molecular mechanisms that regulate SWI/SNF subunit dosage to ensure proper complex assembly remain largely unexplored. We performed a genome-wide CRISPR KO screen, using epigenome editing in mouse embryonic stem cells, and identified Mlf2 and Rbm15 as regulators of SWI/SNF complex activity. First, we show that MLF2, a poorly characterized chaperone protein, regulates a subset of SWI/SNF target genes by promoting its chromatin remodeling activity. Rapid degradation of MLF2 reduces chromatin accessibility at sites that depend on high levels of SWI/SNF binding to maintain open chromatin. Next, we find that RBM15, part of the m6A RNA methylation writer complex, controls m6A modifications on specific SWI/SNF mRNAs to regulate protein levels of these subunits. Misregulation of m6A methylation causes overexpression of core SWI/SNF subunits leading to the assembly of incomplete complexes lacking the catalytic ATPase/ARP subunits. These data indicate that targeting modulators of SWI/SNF complex assembly may offer a potent therapeutic strategy for diseases associated with impaired chromatin remodeling.
2025-04-28 | PXD054392 | Pride
Project description:The SWI/SNF (or BAF) complex is an essential chromatin remodeler that regulates DNA accessibility at developmental genes and enhancers. SWI/SNF subunits are among the most frequently mutated genes in cancer and neurodevelopmental disorders. These mutations are often heterozygous loss-of-function alleles, indicating a dosage-sensitive role for SWI/SNF subunits in chromatin regulation. However, the molecular mechanisms that regulate SWI/SNF subunit dosage to ensure proper complex assembly remain largely unexplored. We performed a genome-wide CRISPR KO screen, using epigenome editing in mouse embryonic stem cells, and identified Mlf2 and Rbm15 as regulators of SWI/SNF complex activity. First, we show that MLF2, a poorly characterized chaperone protein, regulates a subset of SWI/SNF target genes by promoting its chromatin remodeling activity. Rapid degradation of MLF2 reduces chromatin accessibility at sites that depend on high levels of SWI/SNF binding to maintain open chromatin. Next, we find that RBM15, part of the m6A RNA methylation writer complex, controls m6A modifications on specific SWI/SNF mRNAs to regulate protein levels of these subunits. Misregulation of m6A methylation causes overexpression of core SWI/SNF subunits leading to the assembly of incomplete complexes lacking the catalytic ATPase/ARP subunits. These data indicate that targeting modulators of SWI/SNF complex assembly may offer a potent therapeutic strategy for diseases associated with impaired chromatin remodeling.
2025-04-28 | PXD061408 | Pride
Project description:The SWI/SNF ATP-dependent chromatin remodeler is a master regulator of the epigenome; controlling pluripotency, cell fate determination and differentiation. There is a sparsity of information on the autoregulation of SWI/SNF, the domains involved and their mode of action. We find a DNA or RNA binding module conserved from yeast to humans located in the C-terminus of the catalytic subunit of SWI/SNF called the AT-hook that positively regulates the chromatin remodeling activity of yeast and mouse SWI/SNF. The AT-hook in yeast SWI/SNF interacts with the SnAC and ATPase domains, which after binding to nucleosome switches to contacting the N-terminus of histone H3. Deletion of the AT-hooks in yeast SWI/SNF and mouse esBAF complexes reduces the remodeling activity of SWI/SNF without affecting complex integrity or its recruitment to nucleosomes. In addition, deletion of the AT-hook impairs the ATPase and nucleosome mobilizing activities of yeast SWI/SNF without disrupting the interactions of the ATPase domain with nucleosomal DNA. The AT-hook is also important in vivo for SWI/SNF-dependent response to amino acid starvation in yeast and for cell lineage priming in mouse embryonic stem cells. In summary, the AT-hook is shown to be an evolutionarily conserved autoregulatory domain of SWI/SNF that positively regulates SWI/SNF both in vitro and in vivo.
2023-06-15 | PXD040664 | Pride
Project description:Tissue-specific transcription factors initiate differentiation toward a specialized cell type by inducing transcription-permissive chromatin modifications at target gene promoters, through the recruitment of the SWI/SNF chromatin-remodeling complex (1, 2). The molecular mechanism that regulates the chromatin re-distribution of SWI/SNF in response to differentiation signals is currently unknown. Here we show that the muscle determination factor MyoD and the SWI/SNF structural sub-unit, BAF60c (SMARCD3), form a complex on the regulatory elements of MyoD-target genes in undifferentiated myoblasts, prior to the activation of gene expression. MyoD-BAF60c complex is devoid of the ATP-dependent enzymatic sub-units Brg1 and Brm, is required for stable MyoD binding to Ebox sequences, and marks the chromatin for signal-dependent recruitment of the SWI/SNF core complex to muscle loci. BAF60c phosphorylation on a conserved threonine by differentiation-activated p38 signalling promotes the incorporation of MyoD-BAF60c into a Brg1-based SWI/SNF complex, which is competent to remodel the chromatin and activates transcription of MyoD-target genes. Our data support an unprecedented two-step model, by which pre-assembled BAF60c-MyoD complex directs the SWI/SNF complex chromatin re-distribution to muscle loci in response to differentiation cues. Differentiation of C2C12 cells individually interfered for BRG1, BAF60B, BAF60C
2011-03-07 | E-GEOD-24573 | biostudies-arrayexpress
Project description:The SWI/SNF (or BAF) complex is an essential chromatin remodeler that regulates DNA accessibility at developmental genes and enhancers. SWI/SNF subunits are among the most frequently mutated genes in cancer and neurodevelopmental disorders. These mutations are often heterozygous loss-of-function alleles, indicating a dosage-sensitive role for SWI/SNF subunits in chromatin regulation. However, the molecular mechanisms that regulate SWI/SNF subunit dosage to ensure proper complex assembly remain largely unexplored. We performed a genome-wide CRISPR KO screen, using epigenome editing in mouse embryonic stem cells, and identified Mlf2 and Rbm15 as regulators of SWI/SNF complex activity. First, we show that MLF2, a poorly characterized chaperone protein, regulates a subset of SWI/SNF target genes by promoting chromatin remodeling activity. Next, we find that RBM15, part of the m6A RNA methylation writer complex, controls m6A modifications on specific SWI/SNF mRNAs to regulate protein levels of these subunits. Misregulation of m6A methylation causes overexpression of core SWI/SNF subunits leading to the assembly of incomplete complexes lacking the catalytic ATPase/ARP subunits. These data indicate that targeting modulators of SWI/SNF complex assembly may offer a potent therapeutic strategy for diseases associated with impaired chromatin remodeling.
2025-04-28 | GSE268206 | GEO
Project description:PBRM1 is lost in 40% of clear cell renal cell carcinomas (ccRCC) and the combined loss of VHL and PBRM1 drives ccRCC tumorigenesis. PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and despite its well-established role as a tumor suppressor, we have limited understanding of how PBRM1 regulates the chromatin. Now we report that PBRM1 binds to promoter-proxy regions with footprints at +1 to + 3 nucleosomes. PBRM1-deficient PBAF complexes lose BRD7 but retain ARID2, while tethered to SMARCA4. The lack of PBRM1-BRD7 module compromises the targeting specificity of the PBAF complexes, causes their genomic redistribution and impairs the repressive ability of PBAF complexes. Subsequently, PBRM1-deficient PBAF complexes prime the chromatin at de novo sites for transcriptional activation of pro-survival genes involved in hypoxia and cholesterol synthesis. Therefore, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-survival genes by residual PBRM1-deficient SWI/SNF complexes.
| PXD020553 | JPOST Repository
Project description:PBRM1 is lost in 40% of clear cell renal cell carcinomas (ccRCC) and the combined loss of VHL and PBRM1 drives ccRCC tumorigenesis. PBRM1 is an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and despite its well-established role as a tumor suppressor, we have limited understanding of how PBRM1 regulates the chromatin. Now we report that PBRM1 binds to promoter-proxy regions with footprints at +1 to + 3 nucleosomes. PBRM1-deficient PBAF complexes lose BRD7 but retain ARID2, while tethered to SMARCA4. The lack of PBRM1-BRD7 module compromises the targeting specificity of the PBAF complexes, causes their genomic redistribution and impairs the repressive ability of PBAF complexes. Subsequently, PBRM1-deficient PBAF complexes prime the chromatin at de novo sites for transcriptional activation of pro-survival genes involved in hypoxia and cholesterol synthesis. Therefore, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-survival genes by residual PBRM1-deficient SWI/SNF complexes.
| PXD020554 | JPOST Repository
Project description:SWI/SNF is a family of multi-subunit chromatin remodelling complexes comprised of BAF, PBAF and ncBAF. These complexes have diverse roles in cellular processes including transcription, replication, and repair, and play an important role in maintaining genome stability, with over 20% of all cancers having deleterious mutations in a SWI/SNF subunit. We modelled SWI/SNF dysfunction in the widely used cell line, RPE1, by engineering loss of function mutations in both shared and complex-specific subunits, as well as using small molecule treatment to acutely degrade or inhibit SWI/SNF. To analyse the functional consequences of this dysfunction, we performed transcriptomic analysis and compared this with whole cell and chromatin-bound proteomes. Strikingly, SWI/SNF-dependent changes in the transcriptome correlated poorly with changes at the protein level, while changes at the whole protein level correlated well with changes in proteins bound to chromatin. Comparative analyses of protein dynamics revealed that both acute and chronic SWI/SNF loss led to decreased association of cohesin and CTCF with chromatin, and that SWI/SNF remodelling activity was required for the maintenance of cohesin on chromatin. Notably, SWI/SNF loss also led to cohesin and CTCF localising to novel regions in the genome, and the patterns of mislocalisation showed subunit-specific patterns, suggesting that different SWI/SNF complexes have non-redundant impacts on cohesin localisation. Importantly, we find that the relationship between SWI/SNF and cohesin is functionally important, and cells lacking SWI/SNF show significant sensitivity to perturbation of cohesin. Our results highlight SWI/SNF complexes as critical regulators of cohesin dynamics and uncover a vulnerability that has therapeutic potential for cancers driven by SWI/SNF dysregulation.
2026-02-20 | PXD065273 | Pride