Myocardin-related transcription factors are required for cardiac development and function
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69726 | GEO | 2015/12/02
SECONDARY ACCESSION(S): PRJNA286287
REPOSITORIES: GEO
Similar Datasets
Project description:To identify in vivo new cardiac SRF target genes and to study the response of these novel genes to SRF overexpression, we employed a cardiac-specific, transgenic mouse model that has a phenotype in young adulthood which resembles that of the typically aged heart. Using this “cardiac aging” model, we identified 207 genes that are important to cardiac function that were differentially expressed in vivo. Among them, 192 genes had SRF binding motifs (56 with CArG and 136 with CArG-like elements) in their promoter region. Fifty-one of 56 genes with classic CArG elements were not previously reported. These SRF target genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes were significantly increased. Using public databases of mouse models of stress, we also found that altered expression of the SRF target genes occurred in these hearts as well. Thus, SRF target genes are actively regulated under various physiological and pathological conditions, including hemodynamic stress. The mild elevation of SRF protein in the rodent heart that is observed during typical adult aging may have a major impact on many SRF target genes, thereby affecting cardiac structure and performance. In addition, these results could help to enhance our understanding of SRF regulation of cellular processes, including metabolic and cytoskeletal function. The generation and characterization of transgenic mice with mild cardiac-specific overexpression of SRF was previously reported (Zhang et al., 2003). At 6 months of age, the transgenic mice manifested cardiac changes suggestive of an “aged heart” (Zhang et al., 2003). Therefore, 6-month-old transgenic and non-transgenic mice were used in this study. Cardiac gene expression in SRF Tg heart was compared to that of wild-type mice.
2011-08-02 | E-GEOD-19874 | biostudies-arrayexpress
Project description:Myocardin-related transcription factors (MRTFs) play a central role in the regulation of actin expression and cytoskeletal dynamics. Stimuli that promote actin polymerization allow for shuttling of MRTFs to the nucleus where they activate serum response factor (SRF), a regulator of actin and other cytoskeletal protein genes. SRF is an essential regulator of skeletal muscle differentiation and numerous components of the muscle sarcomere, but the potential involvement of MRTFs in skeletal muscle development has not been examined. We explored the role of MRTFs in muscle development in vivo by generating mutant mice harboring a skeletal muscle-specific deletion of MRTF-B and a global deletion of MRTF-A. These double knockout (dKO) mice were able to form sarcomeres during embryogenesis. However, the sarcomeres were abnormally small and disorganized, causing skeletal muscle hypoplasia and perinatal lethality. Transcriptome analysis demonstrated dramatic dysregulation of actin genes in MRTF dKO mice, highlighting the importance of MRTFs in actin cycling and myofibrillogenesis. MRTFs were also necessary for the survival of skeletal myoblasts and for the efficient formation of intact myotubes. Our findings reveal a central role for MRTFs in sarcomere formation during skeletal muscle development and point to the potential involvement of these transcriptional coactivators in skeletal myopathies. Gene expression profile was generated comparing wild type (WT) and HSA-Cre, MRTF-A/B double knockout mice, by deep seqencing, with three biological replicates, using Illumina HiSeq 2500.
2016-08-02 | E-GEOD-84063 | biostudies-arrayexpress
Project description:To identify in vivo new cardiac SRF target genes and to study the response of these novel genes to SRF overexpression, we employed a cardiac-specific, transgenic mouse model that has a phenotype in young adulthood which resembles that of the typically aged heart. Using this “cardiac aging” model, we identified 207 genes that are important to cardiac function that were differentially expressed in vivo. Among them, 192 genes had SRF binding motifs (56 with CArG and 136 with CArG-like elements) in their promoter region. Fifty-one of 56 genes with classic CArG elements were not previously reported. These SRF target genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes were significantly increased. Using public databases of mouse models of stress, we also found that altered expression of the SRF target genes occurred in these hearts as well. Thus, SRF target genes are actively regulated under various physiological and pathological conditions, including hemodynamic stress. The mild elevation of SRF protein in the rodent heart that is observed during typical adult aging may have a major impact on many SRF target genes, thereby affecting cardiac structure and performance. In addition, these results could help to enhance our understanding of SRF regulation of cellular processes, including metabolic and cytoskeletal function. The generation and characterization of transgenic mice with mild cardiac-specific overexpression of SRF was previously reported (Zhang et al., 2003). At 6 months of age, the transgenic mice manifested cardiac changes suggestive of an “aged heart” (Zhang et al., 2003). Therefore, 6-month-old transgenic and non-transgenic mice were used in this study.
2011-08-03 | GSE19874 | GEO
Project description:Myocardin-related transcription factors (MRTFs) play a central role in the regulation of actin expression and cytoskeletal dynamics. Stimuli that promote actin polymerization allow for shuttling of MRTFs to the nucleus where they activate serum response factor (SRF), a regulator of actin and other cytoskeletal protein genes. SRF is an essential regulator of skeletal muscle differentiation and numerous components of the muscle sarcomere, but the potential involvement of MRTFs in skeletal muscle development has not been examined. We explored the role of MRTFs in muscle development in vivo by generating mutant mice harboring a skeletal muscle-specific deletion of MRTF-B and a global deletion of MRTF-A. These double knockout (dKO) mice were able to form sarcomeres during embryogenesis. However, the sarcomeres were abnormally small and disorganized, causing skeletal muscle hypoplasia and perinatal lethality. Transcriptome analysis demonstrated dramatic dysregulation of actin genes in MRTF dKO mice, highlighting the importance of MRTFs in actin cycling and myofibrillogenesis. MRTFs were also necessary for the survival of skeletal myoblasts and for the efficient formation of intact myotubes. Our findings reveal a central role for MRTFs in sarcomere formation during skeletal muscle development and point to the potential involvement of these transcriptional coactivators in skeletal myopathies.
2016-08-02 | GSE84063 | GEO
Project description:Myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF), and thereby regulate cytoskeletal gene expression in response to actin dynamics. MRTFs have also been implicated in heat shock protein (hsp) transcription in fly ovaries, but the mechanisms remain unclear. Here we demonstrate that in mammalian cells, MRTFs are dispensable for hsp gene induction. However, the widely used small molecule inhibitors of MRTF/SRF transcription pathway, derived from CCG-1423, efficiently inhibit hsp gene transcription in both fly and mammalian cells also in absence of MRTFs. Quantifying RNA synthesis and RNA polymerase distribution demonstrates that CCG-1423-derived compounds have a genome-wide effect on transcription. Indeed, tracking nascent transcription at nucleotide resolution reveals that CCG-1423-derived compounds reduce RNA polymerase II elongation, and severely dampen the transcriptional response to heat shock. The effects of CCG-1423-derived compounds therefore extend beyond the MRTF/SRF pathway into nascent transcription, opening novel opportunities for their use in transcription research.
2023-09-26 | GSE243873 | GEO
Project description:Myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF), and thereby regulate cytoskeletal gene expression in response to actin dynamics. MRTFs have also been implicated in heat shock protein (hsp) transcription in fly ovaries, but the mechanisms remain unclear. Here we demonstrate that in mammalian cells, MRTFs are dispensable for hsp gene induction. However, the widely used small molecule inhibitors of MRTF/SRF transcription pathway, derived from CCG-1423, efficiently inhibit hsp gene transcription in both fly and mammalian cells also in absence of MRTFs. Quantifying RNA synthesis and RNA polymerase distribution demonstrates that CCG-1423-derived compounds have a genome-wide effect on transcription. Indeed, tracking nascent transcription at nucleotide resolution reveals that CCG-1423-derived compounds reduce RNA polymerase II elongation, and severely dampen the transcriptional response to heat shock. The effects of CCG-1423-derived compounds therefore extend beyond the MRTF/SRF pathway into nascent transcription, opening novel opportunities for their use in transcription research.
2023-10-03 | GSE244231 | GEO
Project description:To control transcription, SRF recruits signal-regulated co-activators, the Ternary Complex Factors (TCFs) and the Myocardin-related Transcription Factors (MRTFs), which compete for a common site on its DNA-binding domain. The TCFs - SAP-1, Elk-1 and Net - are Ets proteins that link SRF activity to Ras-ERK signalling. In contrast, the two MRTFs, MRTF-A and MRTF-B, link SRF activity to Rho-actin signalling. In this novel signalling pathway, the actin-binding MRTF RPEL domain acts as a G-actin sensor, controlling MRTF nuclear accumulation in response to signal-induced depletion of the G-actin pool. Previous studies have suggested that the Ras-ERK signalling and Rho-actin pathways control specific subsets of SRF target genes. We used ChIP-seq and RNA-seq to analyse the immediate-early transcriptional response in NIH3T3 fibroblasts, using pathway-specific inhibitors to identify the contributions of Ras-ERK and Rho-actin signalling Chromatin immunoprecipitation and sequencing (ChIP-seq) in NIH3T3 fibroblast after serum stimulation in presence or absence of LatrunculinB or U0126 drugs and using antibodies against SRF, MRTF-A, MRTF-B, SAP1, ELK1, NET, Pol II, PolII S5P, PolII S2P and total H3. Validation by ChIP-PCR. Strand specific total-RNA-seq following DSN normalisation and validation by qRT-PCR from NIH3T3 stimulated by serum or Cytochalasin D in presence or absence of LatrunculinB and/or U0126 drugs.
2014-04-24 | E-GEOD-45888 | biostudies-arrayexpress
Project description:To control transcription, SRF recruits signal-regulated co-activators, the Ternary Complex Factors (TCFs) and the Myocardin-related Transcription Factors (MRTFs), which compete for a common site on its DNA-binding domain. The TCFs - SAP-1, Elk-1 and Net - are Ets proteins that link SRF activity to Ras-ERK signalling. In contrast, the two MRTFs, MRTF-A and MRTF-B, link SRF activity to Rho-actin signalling. In this novel signalling pathway, the actin-binding MRTF RPEL domain acts as a G-actin sensor, controlling MRTF nuclear accumulation in response to signal-induced depletion of the G-actin pool. Previous studies have suggested that the Ras-ERK signalling and Rho-actin pathways control specific subsets of SRF target genes. We used ChIP-seq and RNA-seq to analyse the immediate-early transcriptional response in NIH3T3 fibroblasts, using pathway-specific inhibitors to identify the contributions of Ras-ERK and Rho-actin signalling
2014-04-24 | GSE45888 | GEO
Project description:About one third of dilated cardiomyopathy (DCM) cases are caused by mutations in sarcomere or cytoskeletal proteins. Yet treating the cytoskeleton directly is not possible because drugs that bind to actin are not well tolerated. Mutations in the actin binding protein CAP2 can cause DCM and knockout mice, either whole body (CAP2 KO) or cardiomyocyte specific knockouts (CAP2 CKO), develop DCM with cardiac conduction disease. RNA-seq analysis of CAP2 KO hearts and isolated cardiomyocytes revealed over-activation of fetal genes including serum response factor (SRF) regulated genes such as Myl9 and Acta2 prior to the emergence of cardiac disease. To test if we could treat CAP2 KO mice, we synthesized and tested the SRF inhibitor CCG-1423-8u. CCG-1423-8u reduced expression of the SRF targets Myl9 and Acta2, as well as the biomarker of heart failure, NPPA. The median survival of CAP2 CKO mice was 98 days, while CCG-1423-8u treated CKO mice survived for 116 days and also maintain normal cardiac function longer. These results suggest that some forms of sudden cardiac death and cardiac conduction disease are under cytoskeletal stress and that inhibiting signaling through SRF may benefit DCM by reducing cytoskeletal stress.
2019-02-22 | GSE125603 | GEO
Project description:The transcription factor SRF is a master regulator of growth factor inducible and cytoskeletal gene expression. Two transcription cofactor families, the TCFs & the MRTFs, are responsible for SRF's activity to direct transcriptional programme in response to extracellular signalling through the Ras-ERK and Rho-actin pathways respectively. We are investigating the role of the SRF network in the response to infection, using the Listeria monocytogenes model. We find that inactivation of the network impairs the ability of CD8 T cells to proliferate in response to listeria and to generate memory cells. Surprisingly, the defect reflects impaired MRTF-SRF signalling rather than the TCF-SRF signalling pathway usually associated with proliferation. Moreover, the defec doesn'tt lie downstream of the initial activation of the TCR, appearing instead to arise from an inability of CD8 T cells to present IL-2 to each other in paracrine fashion. Consistent with these observations, we find that while cultured CD8 MRTF-null T cells can be effectively activated by TCR crosslinking invitro, their ability to form clusters, which is IL-2-dependent, is impaired. Moreover, as expected, pilot experiments indicate that these cells exhibit deficits both in the basal levels of MRTF-SRF target gene expression, and in their ability to induce these genes in response to IL-2 stimulation:
2023-10-23 | GSE241689 | GEO