Differential roles of copper-binding transcription factors and the subfamilies of the SWI/SNF complex in the transcriptional regulation of the skeletal muscle lineage
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE253379 | GEO | 2024/10/26
REPOSITORIES: GEO
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Project description:Copper (Cu)-binding transcription factors are emerging as important regulators of gene expression during skeletal muscle differentiation. Our group has shown that the classic Metal Transcription Factor 1, MTF1, works cooperatively with the myogenic factor MyoD to promote skeletal muscle differentiation and ensure viability of murine primary myoblasts. Preliminary evidence showed that MTF1 interacts with members of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) family of ATP-dependent chromatin remodeling enzymes to promote differential gene expression in proliferating and differentiating myoblasts. mSWI/SNF complexes are assembled into three major subfamilies that are distinguished by the presence of mutually exclusive subunits: cBAF (canonical BRG1 or BRM-Associated Factor), PBAF (Polybromo containing BAF), or ncBAF (non-canonical BAF). The mechanisms by which each subfamily contributes to the establishment or function of specific cell lineages are poorly understood. We determined the contributions of the BAF, ncBAF, and PBAF complexes to myoblast proliferation, differentiation, and metal homeostasis via knock-down (KD) of a distinguishing subunit of each complex (Baf250A, Brd9, and Baf180, respectively). Biochemical, molecular and RNA-seq analyses showed that Baf250A KD reduced myoblast proliferation rate and differentiation. Brd9 KD resulted in a minor proliferation defect and a delay in myogenesis. KD of Baf180 and other PBAF-specific subunits did not impact proliferation or differentiation but affected the maintenance of metal homeostasis in myoblasts. The data support a model for differential roles and interactions between MTF1 and a novel category of Cu-binding transcription factors and the SWI/SNF enzymes in the development and homeostasis of the skeletal muscle lineage.
2024-10-26 | GSE253377 | GEO
Project description:Copper (Cu)-binding transcription factors are emerging as important regulators of gene expression during skeletal muscle differentiation. Our group has shown that the classic Metal Transcription Factor 1, MTF1, works cooperatively with the myogenic factor MyoD to promote skeletal muscle differentiation and ensure viability of murine primary myoblasts. Preliminary evidence showed that MTF1 interacts with members of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) family of ATP-dependent chromatin remodeling enzymes to promote differential gene expression in proliferating and differentiating myoblasts. mSWI/SNF complexes are assembled into three major subfamilies that are distinguished by the presence of mutually exclusive subunits: cBAF (canonical BRG1 or BRM-Associated Factor), PBAF (Polybromo containing BAF), or ncBAF (non-canonical BAF). The mechanisms by which each subfamily contributes to the establishment or function of specific cell lineages are poorly understood. We determined the contributions of the BAF, ncBAF, and PBAF complexes to myoblast proliferation, differentiation, and metal homeostasis via knock-down (KD) of a distinguishing subunit of each complex (Baf250A, Brd9, and Baf180, respectively). Biochemical, molecular and RNA-seq analyses showed that Baf250A KD reduced myoblast proliferation rate and differentiation. Brd9 KD resulted in a minor proliferation defect and a delay in myogenesis. KD of Baf180 and other PBAF-specific subunits did not impact proliferation or differentiation but affected the maintenance of metal homeostasis in myoblasts. The data support a model for differential roles and interactions between MTF1 and a novel category of Cu-binding transcription factors and the SWI/SNF enzymes in the development and homeostasis of the skeletal muscle lineage.
2024-10-26 | GSE253376 | GEO
Project description:Differential roles of copper-binding transcription factors and the subfamilies of the SWI/SNF complex in the transcriptional regulation of the skeletal muscle lineage
| PRJNA1065431 | ENA
Project description:Lineage switching can induce therapy resistance in cancer. Yet, how lineage fidelity is maintained and how it can be lost remain poorly understood. Here, we have used CRISPR-Cas9-based genetic screening to demonstrate that loss of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, can confer an advantage to clear cell renal cell carcinoma (ccRCC) cells upon inhibition of the renal lineage factor PAX8. Lineage factor inhibition-resistant ccRCC cells formed tumors with morphological features, but not molecular markers, of neuroendocrine differentiation. SMARCB1 inactivation led to large-scale loss of kidney-specific epigenetic programs and restoration of proliferative capacity through the adoption of new dependencies on factors that represent rare essential genes across different cancers. We further developed an analytical approach to systematically characterize lineage fidelity using large-scale CRISPR-Cas9 data. An understanding of the rules that govern lineage switching could aid the development of more durable lineage factor-targeted and other cancer therapies.
| S-EPMC10405256 | biostudies-literature
Project description:Differential roles of copper-binding transcription factors and the subfamilies of the SWI/SNF complex in the transcriptional regulation of the skeletal muscle lineage [RNA-seq]
| PRJNA1065434 | ENA
Project description:Differential roles of copper-binding transcription factors and the subfamilies of the SWI/SNF complex in the transcriptional regulation of the skeletal muscle lineage [CUT&RUN]
| PRJNA1065432 | ENA
Project description:Genes encoding subunits of SWI/SNF (BAF) chromatin remodelling complexes are collectively altered in over 20% of human malignancies, but the mechanisms by which these complexes alter chromatin to modulate transcription and cell fate are poorly understood. Utilizing mouse embryonic fibroblast and cancer cell line models, here we show via ChIP-seq and biochemical assays that SWI/SNF complexes are preferentially targeted to distal lineage specific enhancers and interact with p300 to modulate histone H3 lysine 27 acetylation. We identify a greater requirement for SWI/SNF at typical enhancers than at most super-enhancers and at enhancers in untranscribed regions than in transcribed regions. Our data further demonstrate that SWI/SNF-dependent distal enhancers are essential for controlling expression of genes linked to developmental processes. Our findings thus establish SWI/SNF complexes as regulators of the enhancer landscape and provide insight into the roles of SWI/SNF in cellular fate control.
| S-EPMC5343482 | biostudies-literature
Project description:A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate, and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function, and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate, we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5' ends, RNA Polymerases II and III, and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins, and DNA replication origins). Interestingly we also find that certain configurations of SWI/SNF subunits are associated with transcripts that have higher levels of expression, whereas other configurations of SWI/SNF factors are associated with transcripts that have lower levels of expression. To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins, we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members, as well as with cellular constituents such as nuclear matrix proteins, key transcription factors, and centromere components, implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated.
| S-EPMC3048368 | biostudies-literature
Project description:Lineage-committed cells of many tissues exhibit substantial plasticity in contexts such as wound healing and tumorigenesis, but the regulation of this process is not well understood. We identified the Hippo transducer WWTR1/TAZ in a screen of transcription factors that are able to prompt lineage switching of mammary epithelial cells. Forced expression of TAZ in luminal cells induces them to adopt basal characteristics, and depletion of TAZ in basal and/or myoepithelial cells leads to luminal differentiation. In human and mouse tissues, TAZ is active only in basal cells and is critical for basal cell maintenance during homeostasis. Accordingly, loss of TAZ affects mammary gland development, leading to an imbalance of luminal and basal populations as well as branching defects. Mechanistically, TAZ interacts with components of the SWI/SNF complex to modulate lineage-specific gene expression. Collectively, these findings uncover a new role for Hippo signaling in the determination of lineage identity through recruitment of chromatin-remodeling complexes.
| S-EPMC4011189 | biostudies-literature
Project description:SWItch/Sucrose NonFermentable (SWI/SNF) is a set of multi-subunits chromatin remodeling complexes, playing important roles in a variety of biological processes. Loss-of-function mutations in the genes encoding SWI/SNF subunits have been reported in more than 20% of human cancers. Thus, it was widely considered as a tumor suppressor in the past decade. However, recent studies reported that some genes encoding subunits of SWI/SNF complexes were amplified and play oncogenic roles in human cancers. In present study, we summarized the genetic alteration spectrum of SWI/SNF complexes, and firstly systematically estimated both the copy number variations and point mutations of all 30 genes encoding the subunits in this complex. Additionally, the bioinformatics analyses were performed for two significantly amplified genes, ACTL6A and BRD9, to investigate their oncogenic roles in human cancers. Our findings may lay a foundation for the discovery of potential treatment targets in SWI/SNF complexes of cancers.
| S-EPMC6736241 | biostudies-literature