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RNA-sequencing of rbpms2a; rbpms2b double-mutant and control-sibling zebrafish embryos at 33 hours post fertilization.

ABSTRACT: The identification of novel cardiomyocyte-intrinsic factors that support ventricular function will expand the number of candidate genes and therapeutic options for heart failure, a leading cause of death worldwide. Here, we demonstrate that a conserved RNA-binding protein RBPMS2 is required for ventricular function in zebrafish and for myofibril organization and the regulation of intracellular calcium dynamics in zebrafish and human cardiomyocytes. A differential expression screen uncovered co-expression of rbpms2a and rbpms2b in zebrafish cardiomyocytes. Double knockout embryos suffer from compromised ventricular filling during the relaxation phase of the cardiac cycle, which significantly reduces cardiac output. Evaluating rbpms2-null embryos with splicing-sensitive differential expression analysis, quantitative PCR, and in situ hybridization revealed differential alternative splicing of cardiomyopathy genes including myosin binding protein C3 (mybpc3) and phospholamban (pln). Cardiomyocytes in double mutant ventricles and those derived from RBPMS2-null human induced pluripotent stem cells exhibit myofibril disarray and calcium handling abnormalities. Taken together, our data suggest that RBPMS2 performs a conserved role in regulating alternative splicing in cardiomyocytes, which is required for sarcomere organization, optimal calcium handling, and cardiac function.

ORGANISM(S): Danio rerio

PROVIDER: GSE167414 | GEO | 2022/09/04

REPOSITORIES: GEO

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RNA-sequencing analysis of ZsYellow-negative cells and ZsYellow-positive cardiopharyngeal progenitors and cardiomyocytes purified from the same 14-16 somites stage Tg(nkx2.5:ZsYellow) zebrafish embryos

Project description:The identification of novel cardiomyocyte-intrinsic factors that support ventricular function will expand the number of candidate genes and therapeutic options for heart failure, a leading cause of death worldwide. Here, we demonstrate that a conserved RNA-binding protein RBPMS2 is required for ventricular function in zebrafish and for myofibril organization and the regulation of intracellular calcium dynamics in zebrafish and human cardiomyocytes. A differential expression screen uncovered co-expression of rbpms2a and rbpms2b in zebrafish cardiomyocytes. Double knockout embryos suffer from compromised ventricular filling during the relaxation phase of the cardiac cycle, which significantly reduces cardiac output. Evaluating rbpms2-null embryos with splicing-sensitive differential expression analysis, quantitative PCR, and in situ hybridization revealed differential alternative splicing of cardiomyopathy genes including myosin binding protein C3 (mybpc3) and phospholamban (pln). Cardiomyocytes in double mutant ventricles and those derived from RBPMS2-null human induced pluripotent stem cells exhibit myofibril disarray and calcium handling abnormalities. Taken together, our data suggest that RBPMS2 performs a conserved role in regulating alternative splicing in cardiomyocytes, which is required for sarcomere organization, optimal calcium handling, and cardiac function.

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MED12cKO heart ventricles from male mice [RNA-seq]

Project description:The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is comprised of four proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and found that MED12 localizes to transcription factor consensus sequences within calcium handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes, and that MED12 and MEF2 co-occupy promoters of calcium handling genes. Furthermore, we demonstrated that MED12 enhances MEF2 transcriptional activity and overexpression of both increases expression of calcium handling genes in cardiomyocytes. Our data support a role for MED12 as a coordinator of transcription through MEF2 and other transcription factors. We conclude that MED12 is a regulator of a network of calcium handling genes, consequently “mediating” contractility in the mammalian heart.

2017-08-11 | GSE100088 | GEO

MED12cKO heart ventricles from male mice [ChIP-seq]

2017-08-11 | GSE100087 | GEO

Interplay between calcium cycling and sarcomeres directs cardiomyocyte redifferentiation and maturation during regeneration

Project description:Zebrafish hearts can regenerate by replacing damaged tissue with new cardiomyocytes. Although the steps leading up to the proliferation of surviving cardiomyocytes have been extensively studied, little is known about the mechanisms that control proliferation and redifferentiation to a mature state. We found that the cardiac dyad, a structure that regulates calcium handling and excitation-contraction coupling, played a key role in the redifferentiation process. A component of the cardiac dyad called leucine-rich repeat–containing 10 (Lrrc10) acted as a negative regulator of proliferation, prevented cardiomegaly, and induced redifferentiation. We found that its function was conserved in mammalian cardiomyocytes. This study highlights the importance of the underlying mechanisms required for heart regeneration and their application to the generation of fully functional cardiomyocytes.

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Microarray expression analysis of hearts of zebrafish tremblor mutants at 48 hpf compared to wild-type siblings.

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2017-09-20 | E-MTAB-5850 | biostudies-arrayexpress

Secreted-frizzled-related protein 5 modulates calcium handling in human iPSC-cardiomyocytes

Project description:End-stage heart failure caused by myocardial injury is a leading cause of death in the developed world, with high prevalence and poor prognosis. Current therapies focus on attenuating cardiac remodeling after a cardiovascular event such as myocardial infarction or pressure overload, but no therapy is currently available to halt or reverse disease progression. Recent studies have suggested a cardioprotective function of the Wnt5a inhibitor secreted frizzled-related protein 5 (SFRP5) in preventing adverse cardiac remodeling. However, until now, the underlying molecular mechanisms of SFRP5 treatment in the human heart are not well understood. In this study, we investigated the mechanistic and functional consequences of SFRP5 by establishing knockout and overexpression models in human iPSC-derived cardiomyocytes. Transcriptome profiling and deep pathway analysis revealed an involvement of SFRP5 in the regulation of calcium handling, cardiac contraction, and apoptosis. Functional analysis of iPSC-cardiomyocytes by live-cell calcium imaging confirmed the regulatory role of SFRP5 on calcium homeostasis. Our study uncovered a novel role of SFRP5 as a modulator of calcium handling, providing a deeper molecular understanding of the cardioprotective role of SFRP5 in the human heart.

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Title Page Cardiac Gene Therapy Rescues Diabetic Cardiomyopathy and Lowers Blood Glucose

Project description:Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intra-cardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalizes components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalizes insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescues cardiac lusitropy, improves exercise intolerance, and ameliorates hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy, and also improve systemic glycemic control.

2023-10-24 | PXD044236 | Pride

Transcriptome-guided functional analyses reveal novel biological properties and regulatory heirarchy of human embryonic stem cell derived ventricular cardiomyocytes.

Project description:Profiling global gene expression of undifferentiated human embryonic stem cells, artificially derived cardiomyocytes, fetal ventricular cardiomyocytes, and adult ventricular cardiomyocytes to determine transcriptomic variation between these cell types. Total RNA extracted from 10 human samples representing four stages of cardiac development from undifferentiated stem cells to mature adult cardiac tissue.

2013-09-10 | E-GEOD-50704 | biostudies-arrayexpress

RNA sequencing of wild-type and RBPMS2-null human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)

Project description:The goal of this study was to identify differential alternative splicing events in RBPMS2-null hiPSC-CMs.

2022-09-04 | GSE207681 | GEO

Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure

Project description:Background The contribution of glucocorticoids to sexual dimorphism in the heart is essentially unknown. Therefore, we sought to determine the sexually dimorphic actions of glucocorticoid signaling in cardiac function and gene expression. To accomplish this goal, we conducted studies on mice lacking glucocorticoid receptors (GR) in cardiomyocytes (cardioGRKO mouse model). Methods and Results Deletion of cardiomyocyte GR leads to an increase in mortality because of the development of spontaneous cardiac pathology in both male and female mice; however, females are more resistant to GR signaling inactivation in the heart. Male cardioGRKO mice had a median survival age of 6 months. In contrast, females had a median survival age of 10 months. Transthoracic echocardiography data showed phenotypic differences between male and female cardioGRKO hearts. By 3 months of age, male cardioGRKO mice exhibited left ventricular systolic dysfunction. Conversely, no significant functional deficits were observed in female cardioGRKO mice at the same time point. Functional sensitivity of male hearts to the loss of cardiomyocyte GR was reversed following gonadectomy. RNA‐Seq analysis showed that deleting GR in the male hearts leads to a more profound dysregulation in the expression of genes implicated in heart rate regulation (calcium handling). In agreement with these gene expression data, cardiomyocytes isolated from male cardioGRKO hearts displayed altered intracellular calcium responses. In contrast, female GR‐deficient cardiomyocytes presented a response comparable with controls. Conclusions These data suggest that GR regulates calcium responses in a sex‐biased manner, leading to sexually distinct responses to stress in male and female mice hearts, which may contribute to sex differences in heart disease, including the development of ventricular arrhythmias that contribute to heart failure and sudden death.

2019-12-30 | GSE120573 | GEO

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