Loss of CBP in newborn neurons interferes with synaptic maturation and SRF-dependent neuronal growth
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ABSTRACT:
PROVIDER: PRJNA484954 | ENA |
REPOSITORIES: ENA
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Project description:We used genome-wide sequencing methods to study the consequences of eliminating the CREB-binding protein (CBP) in newborn neurons. We found that CBP-deficient newborn neurons show impaired growth and activity-dependent transcription. In particular, genes downstream of the serum response factor (SRF) and related to neuronal growth and activity-dependent plasticity were affected. The expression of a constitutively active SRF protein with the ability to transactivate target genes in a CBP-independent manner reduced the growth and transcriptional defects associated with CBP ablation.
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2004-11-15 | GSE1948 | GEO
Project description:The objective of the study is to caracherize the genes that are regulated by Srf in myoblasts at day 0 (J0) and in differentiated cells at day 1 (J1) and day 3 (J3). We used microarrays to investigate gene expression in Srf KO and Srf WT muscle cells at day 0 (J0), day 1 (J1) and day 3 (J3) of differentiation
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Project description:The nucleotide analogue azacitidine (AZA) interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. Thus, response-predicting biomarkers and new treatment options are urgently needed to improve the clinical management of these patients. Here, we performed a loss-of-function shRNA screen in combination with AZA treatment in a MDS-derived AML cell line to identify chromatin regulators affecting drug response. We identified the histone acetyl transferase and transcriptional co-activator CBP as a major regulator of AZA sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this affect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cycle progression. Taken together, our results identify a novel synergistic interaction between CBP inhibitors and specifically AZA that warrants further evaluation for the combinatorial treatment of high-risk MDS patients. Beyond the scope of MDS and AZA, we provide novel insight in the function of clinically promising CBP inhibitors that is related to unexpected interference with the translational machinery.
2021-09-22 | PXD021738 | Pride
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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Project description:Empty vector, SRF-dM-VP16 (control construct lacking the SRF DNA binding domain), or SRF-VP16 were expressed in wild-type ES cells (E14wt), SRF heterozygotes (E99-/+) or two SRF ko cell lines (E81-/-,E100-/-). RNA was harvested 72h after transfection. Each condition was performed in duplicate, except E100-/- vector transfected.
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Project description:Serum response factor (SRF) is a transcription factor that binds to the serum response element (SRE) of genes that are expressed in response to mitogens. SRF plays essential roles in muscle and nervous system development; however, little is known about the role of SRF during liver growth and function. To examine the function of SRF in the liver, we generated mice in which the Srf gene was specifically disrupted in hepatocytes. The survival of mice lacking hepatic SRF activity was lower than that of control mice; moreover, surviving mutant mice were smaller and had lower blood glucose and triglyceride levels compared with control mice. Srf-deficient livers were also smaller than control livers, hepatocyte morphology was abnormal, and liver-cell proliferation and viability was compromised. Gene array and quantitative RT-PCR analysis of SRF depleted livers revealed a reduction in mRNAs encoding components of the growth hormone/IGF1 pathway, cyclins, several metabolic regulators, and cytochrome p450 enzymes. Conclusion: SRF is essential for hepatocyte proliferation and survival, liver function, and control of postnatal body growth by regulating hepatocyte gene expression.
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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:Identification of genes whose expression is dependent upon Srf activation within myotubes
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