Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA263913 | ENA |
REPOSITORIES: ENA
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Project description:Members of the CUG-BP, Elav-like family (CELF) regulate alternative splicing in the heart. In MHC-CELFdelta transgenic mice, CELF splicing activity is inhibited postnatally in heart muscle via expression of a nuclear dominant negative CELF protein under an a-myosin heavy chain promoter. MHC-CELFdelta mice develop dilated cardiomyopathy characterized by alternative splicing defects, enlarged hearts, and severe contractile dysfunction. In this study, gene expression profiles in the hearts of wild type, high- and low-expressing lines of MHC-CELFdelta mice were compared using microarrays. Gene ontology and pathway analyses identified contraction and calcium signaling as the most affected processes. Network analysis revealed that the serum response factor (SRF) network is highly affected. Downstream targets of SRF were up-regulated in MHC-CELFdelta mice compared to the wild type, suggesting an increase in SRF activity. Although SRF levels remained unchanged, known inhibitors of SRF activity were down-regulated. These results suggest a role for CELF-mediated alternative splicing in the regulation of contractile gene expression, achieved in part through modulating the activity of SRF, a key cardiac transcription factor. Microarray analysis was performed on total RNA extracted from whole hearts of three MHC-CELFdelta-10 and three MHC-CELFdelta-574 females collected at weaning (three weeks old). Three female wild type littermates from each line were used as controls (n = 6 wild type in total).
2013-08-26 | E-GEOD-40677 | biostudies-arrayexpress
Project description:Members of the CUG-BP, Elav-like family (CELF) regulate alternative splicing in the heart. In MHC-CELFdelta transgenic mice, CELF splicing activity is inhibited postnatally in heart muscle via expression of a nuclear dominant negative CELF protein under an a-myosin heavy chain promoter. MHC-CELFdelta mice develop dilated cardiomyopathy characterized by alternative splicing defects, enlarged hearts, and severe contractile dysfunction. In this study, gene expression profiles in the hearts of wild type, high- and low-expressing lines of MHC-CELFdelta mice were compared using microarrays. Gene ontology and pathway analyses identified contraction and calcium signaling as the most affected processes. Network analysis revealed that the serum response factor (SRF) network is highly affected. Downstream targets of SRF were up-regulated in MHC-CELFdelta mice compared to the wild type, suggesting an increase in SRF activity. Although SRF levels remained unchanged, known inhibitors of SRF activity were down-regulated. These results suggest a role for CELF-mediated alternative splicing in the regulation of contractile gene expression, achieved in part through modulating the activity of SRF, a key cardiac transcription factor.
2013-08-26 | GSE40677 | GEO
Project description:CUG-BP, Elav-like family (CELF) proteins regulate alternative splicing. In MHC-CELFdelta transgenic mice, CELF-mediated alternative splicing is disrupted in heart muscle via expression of a nuclear dominant negative CELF protein under an alpha-myosin heavy chain promoter. MHC-CELFdelta mice develop dilated cardiomyopathy and contractile dysfunction by 3 weeks of age, shortly after the transgene is activated and splicing defects appear. Cardiac function and heart size spontaneously recover with age in a low-expressing (mild) line of MHC-CELFdelta mice despite persistence of dominant negative protein expression and splicing defects, whereas there is no recovery in a higher-expressing (severe) line that also experiences early muscle death and fibrosis. In this study, we explored the basis for this functional recovery by comparing the gene expression profiles in the hearts of low- and high-expressing lines of MHC-CELFdelta mice to those of wild type littermates at 3 weeks (when cardiac dysfunction is maximal) and 24 weeks (when the low-expressing line has recovered) using microarrays. We found that differences in gene expression are greatly reduced in older animals from the low-expressing line, but were exacerbated in the high-expressing line. We did not find evidence of a new compensatory pathway being activated in the low-expressing line with age, and propose that recovery may occur due to developmental stage-specific compatibility of CELF-dependent splice variants with the changing cellular environment of cardiomyocytes. Microarray analysis was performed on total RNA extracted from whole hearts of female mice: three MHC-CELFdelta-10 (high-expressing line) and three MHC-CELFdelta-574 (low-expressing line) were collected at 3 weeks, and five MHC-CELFdelta-10 and five MHC-CELFdelta-574 were collected at 24 weeks. Two wild type mice from each line were collected at each time point (n = 4 total wild type at 3 weeks, and n = 4 total wild type at 24 weeks).
2014-10-16 | E-GEOD-62363 | biostudies-arrayexpress
Project description:CUG-BP, Elav-like family (CELF) proteins regulate alternative splicing. In MHC-CELFdelta transgenic mice, CELF-mediated alternative splicing is disrupted in heart muscle via expression of a nuclear dominant negative CELF protein under an alpha-myosin heavy chain promoter. MHC-CELFdelta mice develop dilated cardiomyopathy and contractile dysfunction by 3 weeks of age, shortly after the transgene is activated and splicing defects appear. Cardiac function and heart size spontaneously recover with age in a low-expressing (mild) line of MHC-CELFdelta mice despite persistence of dominant negative protein expression and splicing defects, whereas there is no recovery in a higher-expressing (severe) line that also experiences early muscle death and fibrosis. In this study, we explored the basis for this functional recovery by comparing the gene expression profiles in the hearts of low- and high-expressing lines of MHC-CELFdelta mice to those of wild type littermates at 3 weeks (when cardiac dysfunction is maximal) and 24 weeks (when the low-expressing line has recovered) using microarrays. We found that differences in gene expression are greatly reduced in older animals from the low-expressing line, but were exacerbated in the high-expressing line. We did not find evidence of a new compensatory pathway being activated in the low-expressing line with age, and propose that recovery may occur due to developmental stage-specific compatibility of CELF-dependent splice variants with the changing cellular environment of cardiomyocytes.
2014-10-16 | GSE62363 | GEO
Project description:Gene expression analysis in mice with heart muscle-specific repression of CELF activity (MHC-CELFdelta)
| PRJNA174626 | ENA
Project description:: The adult heart develops hypertrophy to reduce ventricular wall stress and maintain cardiac function in response to an increased workload. Although pathological hypertrophy generally progresses to heart failure, physiological hypertrophy may be cardioprotective. Cardiac-specific overexpression of the lipid-droplet protein perilipin 5 (Plin5) promotes cardiac hypertrophy, but it is unclear if this response is beneficial. We analyzed human RNA-sequencing data from the left ventricle and showed that cardiac PLIN5 expression correlates with upregulation of cardiac contraction-related processes. To investigate how elevated cardiac Plin5 levels affect cardiac contractility, we generated mice with cardiac-specific overexpression of Plin5 (MHC-Plin5 mice). These mice displayed increased left ventricular mass and cardiomyocyte size but preserved heart function. Quantitative proteomics identified sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) as a Plin5-interacting protein. Phosphorylation of phospholamban, the master regulator of SERCA2, was increased in MHC-Plin5 versus wild-type cardiomyocytes. Live imaging showed increases in intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function in MHC-Plin5 versus wild-type cardiomyocytes. These results identify a role for Plin5 in improving cardiac contractility through enhanced Ca2+ signaling.
2023-01-20 | PXD035121 | Pride
Project description:Presence of ectopic lipid droplets (LDs) in cardiac muscle is associated to lipotoxicity and tissue dysfunction. However, presence of LDs in heart is also observed in physiological conditions, such as at times when cellular energy needs and energy production from mitochondria fatty acid (FA) ?-oxidation are high (fasting). This suggests that development of tissue lipotoxicity and dysfunction is not simply due to the presence of LDs in cardiac muscle but due at least in part to alterations in LD function. To examine the function of cardiac LDs, we obtained transgenic mice with heart-specific plin5 over-expression (MHC-plin5), a member of the perilipin protein family. Hearts from MHC-plin5 mice expressed at least 4-fold higher levels of plin5 and exhibit a 3.5- fold increase in triglyceride content versus non-transgenic littermate. Chronic cardiac excess of LDs was found to result in mild heart dysfunction with decreased expression of PPAR? target genes, decreased mitochondria function and left ventricular concentric hypertrophia. Lack of more severe heart function complications may have been prevented by a strong increased expression of oxidative induced genes via NF-E2-related factor 2 anti-oxidative pathway. Perilipin 5 regulates the formation and stabilization of cardiac LDs, and promotes cardiac steatosis without major heart function impairment. Hearts from Four MCH-Plin5 mice and four control mice at the age of 12 weeks were harvested
2013-02-09 | E-GEOD-44192 | biostudies-arrayexpress
Project description:To determine if the absence of FKBP12 in cardiac tissue alters JPH2 and RYR2 interactions with other dyadic proteins, we immunoprecipitated JPH2 from hearts of FL, MCK-FKD, MHC-Cre+ only, and MHC-FKD mice.
2024-12-04 | MSV000096593 | MassIVE
Project description:Expression data from cardiac CD11c+MHC II+ cells
| PRJNA258442 | ENA
Project description:The Cdk7/cyclin H/menage-a-trois 1 (MAT1) heterotrimer has proposed functions in transcription as the kinase component of basal transcription factor TFIIH and is activated in adult hearts by hypertrophic pathways. Using cardiac-specific Cre, we ablated MAT1 in myocardium. Despite reduced Cdk7 activity, MAT1-deficient hearts grew normally. However, fatal heart failure ensued at 6-8 weeks. By microarray profiling, quantitative RT-PCR, and Western blotting at 4 weeks, genes for energy metabolism were found to be suppressed selectively, including targets of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1). Cardiac metabolic defects were substantiated in isolated perfused hearts and isolated mitochondria. In culture, deleting MAT1 with Cre disrupted PGC-1 function: PGC-1α failed to activate PGC-1-responsive promoters and nuclear receptors, GAL4-PGC-1α was functionally defective, and PGC-1β likewise was deficient. PGC-1 was shown to interact with MAT1 and Cdk7, in co-precipitation assays. Thus, we demonstrate an unforeseen essential role for MAT1 in operation of the PGC-1 family of co-activators. Experiment Overall Design: MAT1F/F mice (Korsisaari et al., 2002) were bred with mice expressing Cre recombinase under the control of the cardiomyocyte-specific α-myosin heavy chain (αMHC) promoter (Gaussin et al., 2002a) and back-bred to MAT1F/F mice to generate the cardiac-specific knockout (αMHC-Cre+/0; MAT1F/F; CKO; Fig. 1A, B). Control mice were αMHC-Cre+/0; MAT1F/+ littermates, differing by the presence of one wild-type MAT1 allele, and excluding Cre-mediated toxicity as a basis for phenotypic disparity. Cardiac RNA samples were analyze at 2 or 4 weeks of age (N = 3-5 for each condition tested.
2009-04-23 | E-GEOD-6662 | biostudies-arrayexpress