SRF promotes long-range chromatin loop formation and stem cell pluripotency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1076243 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27965600_1.fastq.gz | Fastqsanger.gz | |||
| SRR27965600_2.fastq.gz | Fastqsanger.gz | |||
| SRR27965575_1.fastq.gz | Fastqsanger.gz | |||
| SRR27965575_2.fastq.gz | Fastqsanger.gz | |||
| SRR27965576_1.fastq.gz | Fastqsanger.gz |
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Project description:Serum response factor (SRF) is a transcription factor essential for cell proliferation, differentiation, and migration, and is required for primitive streak and mesoderm formation in the embryo. The canonical roles of SRF are mediated by a diverse set of context-dependent cofactors. Here we show that SRF physically interacts with CTCF and cohesin subunits at TAD boundaries and loop anchors. SRF reinforces the insulation of TADs and promotes the formation of long-range chromatin loops. In ES cells, SRF associates with Oct4, Sox2, and Nanog and contributes to the formation of 3D pluripotency hubs. Our findings reveal new roles of SRF in higher-order chromatin organization.
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Project description:Serum response factor (SRF) is a transcription factor essential for cell proliferation, differentiation, and migration, and is required for primitive streak and mesoderm formation in the embryo. The canonical roles of SRF are mediated by a diverse set of context-dependent cofactors. Here we show that SRF physically interacts with CTCF and cohesin subunits at TAD boundaries and loop anchors. SRF reinforces the insulation of TADs and promotes the formation of long-range chromatin loops. In ES cells, SRF associates with Oct4, Sox2, and Nanog and contributes to the formation of 3D pluripotency hubs. Our findings reveal new roles of SRF in higher-order chromatin organization.
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Project description:Multicellular organisms consist of multiple cell types, whose identities are maintained appropriately at locations where they are reside. The identity of each cell type is primarily maintained by cell-type-specific gene expression programs, but mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease β-actin monomer resulted in nuclear accumulation of Mkl1 and the activation of Srf, which downregulated cell-type-specific genes and altered epigenetics in enhancers and chromatin organization. Mice overexpressing Srf exhibited various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.
2018-04-18 | GSE90032 | GEO
Project description:Multicellular organisms consist of multiple cell types, whose identities are maintained appropriately at locations where they are reside. The identity of each cell type is primarily maintained by cell-type-specific gene expression programs, but mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease β-actin monomer resulted in nuclear accumulation of Mkl1 and the activation of Srf, which downregulated cell-type-specific genes and altered epigenetics in enhancers and chromatin organization. Mice overexpressing Srf exhibited various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.
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Project description:Multicellular organisms consist of multiple cell types, whose identities are maintained appropriately at locations where they are reside. The identity of each cell type is primarily maintained by cell-type-specific gene expression programs, but mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease β-actin monomer resulted in nuclear accumulation of Mkl1 and the activation of Srf, which downregulated cell-type-specific genes and altered epigenetics in enhancers and chromatin organization. Mice overexpressing Srf exhibited various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.
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Project description:Multicellular organisms consist of multiple cell types, whose identities are maintained appropriately at locations where they are reside. The identity of each cell type is primarily maintained by cell-type-specific gene expression programs, but mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease β-actin monomer resulted in nuclear accumulation of Mkl1 and the activation of Srf, which downregulated cell-type-specific genes and altered epigenetics in enhancers and chromatin organization. Mice overexpressing Srf exhibited various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.
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2018-04-18 | GSE106315 | GEO
Project description:Multicellular organisms consist of multiple cell types, whose identities are maintained by the locations in which they reside. The identity of a cell is primarily maintained by cell-type-specific gene expression programs, but mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease β-actin monomer quantity resulted in the nuclear accumulation of Mkl1 and the activation of Srf, which downregulated cell-type-specific genes and altered epigenetics in enhancers and chromatin organization. Mice overexpressing Srf exhibited various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.
2018-04-18 | GSE90033 | GEO
Project description:The role of genome organization in the control of gene expression persists as a central mystery of modern biology. Most efforts have focused on the role of boundary elements and CTCF in the compartmentalization of the genome into a series of topological associating domains (TADs). These compartments have been suggested to enable long-range DNA-DNA associations via loop extrusion processes. However, there is emerging evidence for long-range focal contacts, whereby specific DNA sequences associated with promoters and distal enhancers interact to form chromatin loops. One such class of DNAs, tethering elements, binds GAGA-associated factor (GAF). Previous studies provided evidence that GAF possesses amyloid properties in vitro, enabling the formation of loops bridging separate DNA molecules. In this study we investigated the possibility that GAF also functions as a looping factor in Drosophila development. We employed a combination of Micro-C assays, proteasomal degradation, and genome editing to examine the impact of defined GAF mutants on genome topology. These studies suggest that the N-terminal POZ/BTB oligomerization domain is particularly important for long-range interactions of GAF bound to distant GAGA-rich tethering elements. By contrast, the C-terminal low complexity domain (poly Q) plays only a minor role in loop formation. The most striking effects of GAF mutants are observed for long-range promoter-promoter interactions that coordinate the activities of distant paralogous genes.
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Project description:Serum Response Factor (SRF) is a transcriptional regulator required for mesodermal development. Numerous studies have implicated SRF as a central regulator of muscle gene expression and myogenesis. In this present study we used a loss of function approach to delineate the role of SRF in cardiac myocyte gene expression and function. In SRF null neonatal cardiomyocytes, we observe severe defects in the contractile apparatus, including Z-disc and stress fiber formation, as well as mislocalization and/or attenuation of sarcomeric proteins. Consistent with this, gene array and RT-PCR analyses show downregulation of genes encoding key cardiac transcriptional regulatory factors and proteins required for the maintenance of sarcomeric structure, function, and regulation. Chromatin IP analysis reveals that at least a subset of these proteins are likely regulated directly by SRF. Together the results presented here reveal new cellular and genetic mechanisms through which SRF exacts control over the contractile apparatus in cardiac myocytes. Keywords: genetic modification
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