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Isogenic human pluripotent stem cell disease models reveal actin binding Rho activating protein deficiency underlies the cardiac troponin T DK210 mutation-induced familial dilated cardiomyopathy I

ABSTRACT: The cTnT-DK210 DCM mice showed ABRA protein deficiency, sarcomeric disruption, and compromised heart contractility. Heart-specific expression of ABRA in cTnT-DK210 mice restored sarcomeric structures, reversed the disease progress, and rescued the DCM phenotypes. ABRA deficiency and compromised downstream serum response factor-regulated muscle gene expression play a key role in familial DCM caused by the cTnT-DK210 mutation. ABRA is a good therapeutic gene for cTnT-DK210-induced DCM and could be translated to other cTnT mutations-induced familial DCM.

ORGANISM(S): Mus musculus

PROVIDER: GSE154096 | GEO | 2021/10/01

REPOSITORIES: GEO

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Isogenic human pluripotent stem cell disease models reveal actin binding Rho activating protein deficiency underlies the cardiac troponin T DK210 mutation-induced familial dilated cardiomyopathy II

Project description:Different single mutations on the same sarcomeric gene often cause distinct cardiomyopathy phenotypes as dilated (DCM) or hypertrophic cardiomyopathy (HCM). The key factors involved in this disease divergence is unknown and could be key for disease intervention.We generated isogenic familial DCM and HCM disease-specific human embryonic stem cells (hESCs) carrying the cTnT-DK210 and -DE160 mutation, respectively. Whole transcriptomic RNA-sequencing was used to identify the key gene involved in the earliest disease divergence of cTnT-DK210 caused DCM and cTnT-DE160 caused HCM. Results provide insight into the new molecular mechanisms underlying familial dilated cardiomyopathy.

2021-10-01 | GSE154097 | GEO

Depletion of m6A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin

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2022-08-01 | GSE164353 | GEO

Expression data from patient iPSC and iPSC-derived cardiomyocytes

Project description:Dilated cardiomyopathy (DCM) is the leading cause of heart failure and transplantation worldwide. We used iPSCs to model this disease and compared gene expression change before and after gene therapy of cardiomyocytes derived from DCM-specific iPSCs. We used microarrays to detail the global gene expression of patient specific iPSCs, iPSC-derived cardiomyocytes and its response to gene therapy. Skin fibroblasts and iPSCs derived from a family exhibiting familial dilated cardiomyopathy and H7 human ESCs were subjected to RNA extraction and hybridization on Affymetrix microarrays.Global gene expression pattern were compared and analyzed. Cardiomyocytes derived from iPSCs generated from this DCM family were treated with or without adenoriral Serca2a and subjected to RNA extraction and hybridization on Affymetrix microarrays. Global gene expression pattern were compared and analyzed.

2012-02-01 | E-GEOD-35108 | biostudies-arrayexpress

microRNA expression data from a heterozygous Titin-deficient mouse model and wildtype controls

Project description:Mutations in the sarcomeric protein titin are a major cause of human dilated cardiomyopathy. We have developed a knock-in mouse model that imitated a previously identified titin truncation mutation. The heterotygous Ttn-deficient mice develop features of DCM and therefore recapitulate the human phenotype. To investigate the role of microRNAs in titin-based heart failure, we performed a miRNA screen in heterozygous Ttn-deficient mice and their wildtype littermate controls.

2017-01-31 | GSE90972 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and cardiac-specific Bmi1 deletion [human]

Project description:To explore the primary cause of Dilated Cardiomyopathy in heart samples from DCM-diagnosed patients who had undergone heart transplant (hDCM), we set out to identify differentially expressed genes by massively parallel sequencing of heart samples. Methods: Heart mRNA profiles from DCM-diagnosed patients who had undergone heart transplant (hDCM) were generated by deep sequencing, in triplicate, using Illumina GAIIx.

2015-01-30 | E-GEOD-65446 | biostudies-arrayexpress

Gene expression levels od Troponin T Amino Acid Mutation (ΔK 210) Knock-in Mice as a Neonatal Dilated Cardiomyopathy Model at 0day and 1week after birth

Project description:Cardiac phenotypes of homozygous ΔK210 knock-in (TNNT2ΔK210/ΔK210) mice including comprehensive gene expression profiles were investigated to establish an animal model of neonatal DCM and to identify early progression factors of pediatric DCM.

2019-06-21 | GSE133052 | GEO

Enhancing Cardiac Cell Proliferation and Survival Suppresses Dilated Cardiomyopathy caused by Ttn-insufficiency

Project description:Dilated cardiomyopathy (DCM), defined by left ventricular (LV) enlargement associated with impaired cardiac performance, is a major cause of heart failure (HF). This results in a dilated, thin-walled left ventricle that fails to supply sufficient blood to the body. Truncating variants in TTN (TTNtv), coding for the largest structural protein in the sarcomere, contribute to the largest portion of familial and ambulatory DCM. The mechanisms for how TTNtv lead to cardiac dilation are unclear. Here, we show that reduction of Ttn expression by shRNA (Ttn shRNA) generated DCM in both mouse and rat. Ttn shRNA transduced mice developed typical DCM manifestations including impaired cardiac performance, enlarged LV and reduced LV wall thickness. Gene profiling indicates cardiac metabolism, cell proliferation and survival related genes are significantly dysregulated in Ttn shRNA-induced DCM. TUNEL assay showed Ttn shRNA induced a significant increase of cardiac cell apoptosis. A screen of 15 dysregulated downstream genes identified candidates, including Esrra, Esrrb and Yy1 significantly suppressed Ttn shRNA-induced cardiac dilation and/or DCM. Ttn shRNA induced cardiac cell apoptosis was ameliorated by Yy1. Importantly, by inducing D-type cyclin, Yy1 initiated cardiomyocyte cell cycle reentry facilitating the restoration of cardiac performance. Our findings demonstrate that DCM caused by Ttn insufficiency can be treated by therapeutically enhancing cardiac cell proliferation and survival.

2020-03-26 | GSE112319 | GEO

Dilated Cardiomyopathy in Dobermans and Boxers

Project description:This study attempts at investigating the changes in cardiac gene expression that occur in Dilated Cardiomyopathy (DCM). DCM in Dobermans and Boxers are the focus of this study. Control heart tissue as well as Pacing tissue used is from mongrel dogs. Keywords: control vs pacing vs disease; strain specific disease 3 Dobermans-DCM, 4 Boxers-DCM, 3 mongrels-control and 3 mongrels-pacing

2008-05-08 | E-GEOD-11015 | biostudies-arrayexpress

The RNA Binding Protein IGF2BP2 is Upregulated by Stress in the Heart and Causes Mitochondrial Dysfunction and Dilated Cardiomyopathy

Project description:The IGF2BP family of RNA binding proteins consists of three paralogs, IGF2BP1, 2, and 3, that regulate RNA function at many levels, including intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. Several previous studies indicated that IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodelling and returns to normal levels in recovering hearts. These results suggested that IGF2BP2 might play an adaptive role during cardiac stress and recovery. To investigate the role of IGF2BP2 in the heart, we made use of a conditional, inducible transgenic mouse line. Enhanced expression of the IGF2BP2 transgene in hearts of newborn or adult mice leads to dilated cardiomyopathy (DCM), with remodelling, fibrosis, and death occurring within 3-4 weeks. Turning off expression of the transgene after 2 weeks, however, rescues these mice, and they recover completely by 12 weeks. Proteomic analysis identified a downregulation of sarcomeric and mitochondrial proteins in hearts overexpressing IGF2BP2, and electron microscopy revealed fragmented mitochondria and elongated, thinner sarcomeres, suggesting a possible mechanism of action. Consistent with these results, IGF2BP2 is upregulated in patients with DCM or after myocardial infarction. These results show that cardiac stress upregulates IGF2BP2, and this upregulation causes remodelling and compensation of the heart. Prolonged IGF2BP2 expression, however, leads to heart failure and death, making it an attractive target for therapeutic intervention.

2024-01-26 | PXD037623 | Pride

Genome-wide chromatin state in non-failing and dilated cardiomyaphty human left ventricles [PLAC-seq]

Project description:We conducted chromatin immunoprecipitation followed by sequencing (ChIP-seq) and proximity ligation-assisted ChIP-seq (PLAC-seq) for enhancers and promoters (E-P) using left ventricular tissues from dilated cardiomyopathy (DCM) patients and non-heart failure (NF) donors. Differential active enhancer H3K27ac and promoter H3K4me3 regions were identified between NF and DCM. While the average read density (ARD) for H3K27ac is similar between NF and DCM, the ARD of H3K4me3 is significantly lower in DCM samples than in NF.Super-enhancer (SE) analysis revealed that 929 and 129 genes linked to NF- and DCM-specific SE, respectively, and three unique SE-associated genes between NF and DCM were identified.Moreover, the differential E-P interactions were observed in the known heart failure gene loci and are correlated with the gene expression levels. Motif analysis identified known cardiac factors and possible novel players for DCM. We have established cistrome of four histone modifications and long-range chromatin interaction for enhancers and promoters in NF and DCM tissues. The differential histone modifications and E-P interactions were found in DCM, and these differences were associated with the gene expression level of a subset of disease-associated genes in human heart failure.

2022-01-15 | GSE135954 | GEO

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