A gene regulatory element modulates myosin expression and alters cellular response to stress
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE283430 | GEO | 2025/09/18
REPOSITORIES: GEO
Similar Datasets
Project description:A hallmark of heart disease is gene dysregulation and reactivation of fetal gene programs. Reactivation of these fetal programs can provide cardioprotective or compensatory effects during heart failure depending on the type and stage of the underlying cardiomyopathy. Many putative cardiac gene regulatory elements have been identified that may control these programs, but their functions are largely unknown. We profile genome-wide changes to gene expression and chromatin structure in cardiomyocytes derived from human pluripotent stem cells. We identify and characterize a gene regulatory element important for the regulation of MYH6 that encodes human fetal myosin and is critical to the pathogenesis of hypertrophic and dilated cardiomyopathies. Using chromatin conformation assays in combination with epigenome editing, we find that gene regulation is mediated through direct interaction between MYH6 and the enhancer. We also find that activation of the enhancer alters cardiomyocyte response to the hypertrophy-inducing peptide endothelin-1. Collectively, these results identify regulatory mechanisms of cardiac gene expression programs that act through critical developmental factors and modulate cellular response to stress.
2025-09-18 | GSE283432 | GEO
Project description:A hallmark of heart disease is gene dysregulation and reactivation of fetal gene programs. Reactivation of these fetal programs can provide cardioprotective or compensatory effects during heart failure depending on the type and stage of the underlying cardiomyopathy. Many putative cardiac gene regulatory elements have been identified that may control these programs, but their functions are largely unknown. We profile genome-wide changes to gene expression and chromatin structure in cardiomyocytes derived from human pluripotent stem cells. We identify and characterize a gene regulatory element important for the regulation of MYH6 that encodes human fetal myosin and is critical to the pathogenesis of hypertrophic and dilated cardiomyopathies. Using chromatin conformation assays in combination with epigenome editing, we find that gene regulation is mediated through direct interaction between MYH6 and the enhancer. We also find that activation of the enhancer alters cardiomyocyte response to the hypertrophy-inducing peptide endothelin-1. Collectively, these results identify regulatory mechanisms of cardiac gene expression programs that act through critical developmental factors and modulate cellular response to stress.
2025-09-18 | GSE283427 | GEO
Project description:A hallmark of heart disease is gene dysregulation and reactivation of fetal gene programs. Reactivation of these fetal programs can provide cardioprotective or compensatory effects during heart failure depending on the type and stage of the underlying cardiomyopathy. Many putative cardiac gene regulatory elements have been identified that may control these programs, but their functions are largely unknown. We profile genome-wide changes to gene expression and chromatin structure in cardiomyocytes derived from human pluripotent stem cells. We identify and characterize a gene regulatory element important for the regulation of MYH6 that encodes human fetal myosin and is critical to the pathogenesis of hypertrophic and dilated cardiomyopathies. Using chromatin conformation assays in combination with epigenome editing, we find that gene regulation is mediated through direct interaction between MYH6 and the enhancer. We also find that activation of the enhancer alters cardiomyocyte response to the hypertrophy-inducing peptide endothelin-1. Collectively, these results identify regulatory mechanisms of cardiac gene expression programs that act through critical developmental factors and modulate cellular response to stress.
2025-09-18 | GSE283424 | GEO
Project description:A hallmark of heart disease is gene dysregulation and reactivation of fetal gene programs. Reactivation of these fetal programs can provide cardioprotective or compensatory effects during heart failure depending on the type and stage of the underlying cardiomyopathy. Many putative cardiac gene regulatory elements have been identified that may control these programs, but their functions are largely unknown. We profile genome-wide changes to gene expression and chromatin structure in cardiomyocytes derived from human pluripotent stem cells. We identify and characterize a gene regulatory element important for the regulation of MYH6 that encodes human fetal myosin and is critical to the pathogenesis of hypertrophic and dilated cardiomyopathies. Using chromatin conformation assays in combination with epigenome editing, we find that gene regulation is mediated through direct interaction between MYH6 and the enhancer. We also find that activation of the enhancer alters cardiomyocyte response to the hypertrophy-inducing peptide endothelin-1. Collectively, these results identify regulatory mechanisms of cardiac gene expression programs that act through critical developmental factors and modulate cellular response to stress.
2025-09-18 | GSE283426 | GEO
Project description:In humans, cardiac hypertrophy is the principal risk factor for the development of overt heart failure and sudden cardiac death from lethal arrhythmias. Although aberrant reactivation of fetal² gene programs is intricately linked to maladaptive hypertrophy of postnatal cardiomyocytes, loss of cardiac function and heart failure, the transcription factors driving these gene programs remain ill defined. We report that the basic helix-loop-helix (bHLH) transcription factor dHAND/Hand2 is re-expressed in the mammalian postnatal myocardium in response to stress signaling. Interestingly, mutant mice overexpressing Hand2 in otherwise healthy ventricular myocytes developed a phenotype of pathological hypertrophy. In contrast, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. These data suggest a critical role for the Hand2 transcription factor during hypertrophic remodeling and heart failure. To gain more mechanistically insight in the processes underlying heart failure, we here identified Hand2 target genes by microarray gene expression profiling. RNA samples were collected 4 weeks after sham or TAC surgery (to induce pressure overload) of both tamoxifen-treated Hand2f/f (WT) and MCM-Hand2f/f (KO) mice.
2013-11-15 | E-MTAB-1821 | biostudies-arrayexpress
Project description:Transposable elements (TEs) have extensively reshaped the cis-regulatory landscape of mammalian genomes, yet the mechanisms that govern their context-specific activity remain incompletely understood. KRAB zinc finger proteins (KZFPs), a large family of transcription factors specialized in TE recognition, are known repressors of TE-derived regulatory activity through TRIM28-mediated H3K9me3 deposition. Here, we expand this paradigm by uncovering noncanonical relationships between TEs and KZFPs. By generating a comprehensive epigenomic map of KZFP-bound TEs, we find that the regulatory activity of ancient mammalian L2/MIR elements is broadly delineated by KZFP binding patterns, despite low H3K9me3 enrichment. We further dissect this relationship by investigating the function of ZNF436, a non-canonical KZFP, highly expressed during in vivo human fetal heart development. Using loss-of-function approaches, we show that ZNF436 preserves cardiomyocyte function by promoting cardiac gene expression while restricting the activation of alternative lineage programs. Mechanistically, ZNF436 recruits specialized SWI/SNF chromatin remodeling complexes to limit the accessibility of L2/MIR-derived enhancers, many of which are active in non-cardiac tissues. These findings reveal a noncanonical, TRIM28-independent role for KZFPs in shaping cell-type-specific regulatory landscapes and emphasize the importance of repressing alternative regulatory programs alongside activating lineage-specific ones to safeguard cell identity.
2025-12-01 | PXD064106 | Pride
Project description:In the current study we examined several proteomic- and RNA-Seq-based datasets of cardiac-enriched, cell-surface and membrane-associated proteins in human fetal and mouse neonatal ventricular cardiomyocytes. By integrating available microarray and tissue expression profiles along with MGI phenotypic analysis, we identified 173 membrane-associated proteins that are cardiac-enriched, conserved amongst eukaryotic species, and have not yet been linked to a ‘cardiac’ Phenotype-Ontology. To highlight the utility of this dataset, we selected several proteins to investigate more carefully, including FAM162A, MCT1, and COX20, to show cardiac enrichment, subcellular distribution and expression patterns in disease. Three-dimensional imaging was used to validate subcellular localization and expression in adult mouse ventricular cardiomyocytes. FAM162A, MCT1, and COX20 were differentially expressed at the transcriptomic and proteomic levels in multiple models of mouse and human heart diseases and may represent potential diagnostic and therapeutic targets for human dilated and ischemic cardiomyopathies. Altogether, we believe this comprehensive cardiomyocyte membrane proteome dataset will prove instrumental to future investigations aimed at characterizing heart disease markers and/or therapeutic targets for heart failure.
2020-11-17 | PXD017732 | Pride
Project description:Background and Objective: Currently, the cells for transplantation were derived from either autologous or allogeneic tissue. The former has a drawback that the quality of donor cells could depend on the patient’s condition, and the quantity could also be limited. To solve these problems, we investigated the potential of allogeneic cardiac mesenchymal progenitors (CMPs) derived from postmortem heart, which might be an immunological privileged like bone marrow-derived mesenchymal progenitors. Materials and Methods: We examined whether viable CMPs could be isolated from murine postmortem cardiac tissue that was harvested 24 hours postmortem. After two to three weeks propagation with high dose of basic fibroblast growth factor, we performed the cellular characteristics analyses, which included proliferation and differentiation property flow cytometric analyses, and microarray analyses. Results: Postmortem CMPs had longer lag phase after seeding than CMPs from living tissues, but they demonstrated the similar characteristics in all above examinations. In addition, global gene expression analysis by microarray indicated the similar characteristics between the cell derived from postmortem and living tissue. Conclusion: These results indicate allogeneic postmortem CMPs could have promising potential for cell transplantation as clinical applications, because of circumventing the issue of brain death. The samples were collected fom living or postmortem cardiac tissue (24 hr at 4C). We generated cardiac mesenchymal progenitors (CMPs) from these cardiac tissue, and compared global gene expression by AgilentMouse GE 8x60k Microarray. Adult, or fetal mouse heart RNAs were used as positive control. Adult mouse total heart RNAs were purchased from Clontech. Fetal mouse heart was extracted from fetus which is embryonic day 16.5 C57BL/6 strain. Tg means Transgenic mouse (C57BL/6-Tg(Myh6-EGFP)MG2).
2013-08-28 | E-GEOD-50221 | biostudies-arrayexpress
Project description:As the fetal heart develops, cardiomyocyte proliferation potential decreases while fatty acid oxidative capacity increases, a highly regulated transition known as cardiac maturation. Small noncoding RNAs, such as microRNAs (miRNAs), contribute to the establishment and control of tissue-specific transcriptional programs. However, small RNA expression dynamics and genome wide miRNA regulatory networks controlling maturation of the human fetal heart remain poorly understood. Transcriptome profiling of small RNAs revealed the temporal expression patterns of miRNA, piRNA, circRNA, snoRNA, snRNA and tRNA in the developing human heart between 8 and 19 weeks of gestation. Our analysis revealed that miRNAs were the most dynamically expressed small RNA species throughout mid-gestation. Cross-referencing differentially expressed miRNAs and mRNAs predicted 6,200 mRNA targets, 2134 of which were upregulated and 4066 downregulated as gestation progresses. Moreover, we found that downregulated targets of upregulated miRNAs predominantly control cell cycle progression, while upregulated targets of downregulated miRNAs are linked to energy sensing and oxidative metabolism. Furthermore, integration of miRNA and mRNA profiles with proteomes and reporter metabolites revealed that proteins encoded in mRNA targets, and their associated metabolites, mediate fatty acid oxidation and are enriched as the heart develops.This study revealed the small RNAome of the maturing human fetal heart. Furthermore, our findings suggest that coordinated activation and repression of miRNA expression throughout mid-gestation is essential to establish a dynamic miRNA-mRNA-protein network that decreases cardiomyocyte proliferation potential while increasing the oxidative capacity of the maturing human fetal heart.
2024-01-26 | PXD044936 | Pride
Project description:Rationale: Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. Objective: The objectives of our study were to determine if myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. Methods and Results: We derived a core transcriptional signature of injury-induced cardiac myocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiac myocyte differentiation, in vitro cardiac myocyte explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of cardiac myocyte differentiation processes including reactivation of latent developmental programs similar to those observed during de-stabilization of a mature cardiac myocyte phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13 (IL13), which induced cardiac myocyte cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of IL13 signaling in cardiac myocytes. These downstream signaling molecules are also modulated in the regenerating mouse heart. Conclusions: Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration. Comparison of transcriptional programs of primary myocardial tissues sampled from neonatal mice and murine hearts undergoing post-injury regeneration, along with in vitro ESC-differentiated cardiomyocytes
2014-12-20 | E-GEOD-64403 | biostudies-arrayexpress