Tead1 is required to maintain adult cardiomyocyte function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE85038 | GEO | 2018/07/13
REPOSITORIES: GEO
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Project description:Adult heart size is determined predominantly by the cardiomyocyte number and size. The cardiomyocyte number is determined primarily in the embryonic and perinatal period, as adult cardiomyocyte proliferation is restricted in comparison to that seen during the perinatal period. Recent evidence has implicated the mammalian Hippo kinase pathway as being critical in cardiomyocyte proliferation. Though the transcription factor, Tead1, is the canonical downstream transcriptional factor of the hippo kinase pathway in cardiomyocytes, the specific role of Tead1 in cardiomyocyte proliferation in the perinatal period has not been determined. Here, we report the generation of a cardiomyocyte specific perinatal deletion of Tead1, using Myh6-Cre deletor mice (Tead1-cKO). Perinatal Tead1 deletion was lethal by postnatal day 9 in Tead1-cKO mice due to dilated cardiomyopathy. Tead1-deficient cardiomyocytes have significantly decreased proliferation during the immediate postnatal period, when proliferation rate is normally high. Deletion of Tead1 in HL-1 cardiac cell line confirmed that cell-autonomous Tead1 function is required for normal cardiomyocyte proliferation. This was secondary to significant decrease in levels of many proteins, in vivo, that normally promote cell cycle in cardiomyocytes. Taken together this demonstrates the non-redundant critical requirement for Tead1 in regulating cell cycle proteins and proliferation in cardiomyocytes in the perinatal heart.
| S-EPMC6392249 | biostudies-literature
Project description:Heart disease remains the leading cause of death worldwide, highlighting a pressing need to identify novel regulators of cardiomyocyte (CM) function that could be therapeutically targeted. The mammalian Hippo/Tead pathway is critical in embryonic cardiac development and perinatal CM proliferation. However, the requirement of Tead1, the transcriptional effector of this pathway, in the adult heart is unknown. Here, we show that tamoxifen-inducible adult CM-specific Tead1 ablation led to lethal acute-onset dilated cardiomyopathy, associated with impairment in excitation-contraction coupling. Mechanistically, we demonstrate Tead1 is a cell-autonomous, direct transcriptional activator of SERCA2a and SR-associated protein phosphatase 1 regulatory subunit, Inhibitor-1 (I-1). Thus, Tead1 deletion led to a decrease in SERCA2a and I-1 transcripts and protein, with a consequent increase in PP1-activity, resulting in accumulation of dephosphorylated phospholamban (Pln) and decreased SERCA2a activity. Global transcriptomal analysis in Tead1-deleted hearts revealed significant changes in mitochondrial and sarcomere-related pathways. Additional studies demonstrated there was a trend for correlation between protein levels of TEAD1 and I-1, and phosphorylation of PLN, in human nonfailing and failing hearts. Furthermore, TEAD1 activity was required to maintain PLN phosphorylation and expression of SERCA2a and I-1 in human induced pluripotent stem cell-derived (iPS-derived) CMs. To our knowledge, taken together, this demonstrates a nonredundant, novel role of Tead1 in maintaining normal adult heart function.
| S-EPMC5621883 | biostudies-literature
Project description:TEAD1 acts as a key molecule of muscle development, and trans-activates multiple target genes involved in cell proliferation and differentiation pathways. However, its target genes in skeletal muscles, regulatory mechanisms and networks are unknown. Here, we use ChIP-on-chip to identify direct target genes of TEAD1. All animal procedures were performed according to protocols approved by Hubei Province, P. R. China for Biological Studies Animal Care and Use Committee. Skeletal muscle tissues were collected from three adult Kunming mice.
2011-02-01 | E-GEOD-26107 | biostudies-arrayexpress
Project description:Purpose: The goal of this study is to determine the regulatory role of tead1 in β-cells by analyzing the transcriptomal changes with Tead1 deletion in β-cells Methods: Isolated islet mRNA profiles of β-cell Tead1 KO mice compared to control floxed mice at 1 year of age were assessed by RNA-seq using Illumina Hiseq2500. The sequence reads that passed quality filters were analyzed at the transcript isoform level using the CLC genomic workbench. qRT-PCR validation was performed using SYBR Green assays Conclusions: Our study represents the first detailed analysis of beta cell transcriptomes following Tead1 deletion in beta cells.
2022-12-14 | GSE139152 | GEO
Project description:Hippo signaling pathway is pivotally involved in human cancer. Among the Hippo components, YAP1 is highly active while function of MST1,2 and SAV1 was lost in liver cancer. Based on systematic analysis, we identified KLF5 as YAP1 binding partner in silico. To investigate KLF5 in liver cancer, we performed the gene expression microarray after knocked down YAP1, TEAD1 and KLF5 in SK-Hep1 cell line. To identify the role of YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line, we performed microarray after knocking down YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line (3 siLuc, 3 siYAP1, 3 siTEAD1, 3 siKLF5)
2013-12-31 | E-GEOD-32597 | biostudies-arrayexpress
Project description:Purpose: The goal of this study is to determine the regulatory role of Tead1 in β-cells by analyzing the Tead1 cistrome and open chromatin in β-cells Methods: Isolated islets from WT C57bl6 mice of 12 weeks of age were flash frozen. For Chip-seq they were fixed with formaldehyde and then after sonication, IP was performed with Anti-Tead1 antibody or the IgG isotype control. For ATAC-seq 100,000 of the frozen nuclei were tagmented. After DNA extraction, library construction, sequencing was performed using Illumina Hi seq2500. Conclusions: Our study represents the first detailed analysis of the Tead1 cistrome in beta cells.
2022-12-14 | GSE157513 | GEO
Project description:Tead1 is a transcription factor downstream of the hippo pathway. Gene expression is compared between whole islets from beta cell specific tead1 KO (using Rip-Cre) and Floxed control islets
2022-12-14 | GSE139228 | GEO
Project description:Cardiac fibroblasts (CFs) are the primary cells tasked with extracellar matrix reorganization and significantly associated with heart failure (HF). Previous studies have shown that TEAD1 deficiency deteriorated heart development and homeostasis. However, the role of TEAD1 in fibroblasts during cardiac remodeling was still undiscovered. Our study demonstrated that TEAD1 was upregulated predominently in cardiac fibroblasts in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency ameliorated TAC-induced cardiac remodeling and treatment with TEAD1 inhibitor, VT103, mimiced this phenotypic effect. Mechanistically, RNA-seq analysis , ChIP-Seq analysis identified TEAD1 promotes the fibroblast-to-myofibroblast transition through the Wnt signalling pathway. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.
2024-01-15 | GSE253118 | GEO
Project description:In this work, we generated a new human induced-pluripotent stem cells derived-cardiomyocytes (hiPSC-CM); in this new hiPSC-CM cell line, Cyclin D2 (CCND2), a cell-cycle activator, was overexpressed, and class I-II of major histocompatibility complex were knocked down. This new cell line (named KO/OEhiPSC-CM) and the wildtype hiPSC-CM (name WThiPSC-CM) were transplanted into pig hearts with ischemic-reperfusion (I/R). The objective is to examine engraftment, cardiac function change, and how the host (pig) heart responded to the transplantation. Surprisingly, while the pig hearts receiving KO/OEhiPSC-CM showed significant cardiac function 4 weeks after I/R, the KO/OEhiPSC-CM grafts were undetectable. Analyzing the single-nuclei RNA sequencing (SnRNAseq) data of these pig hearts showed that 1) the host cardiomyocyte actively reentered cell-cycle, which was among the key factors for cardiac function improvement; 2) this effect was mediated via HIPPO/YAP signaling pathway; and 3) HIPPO/YAP signaling pathway activity was a result of Follistatin (FST) secreted by the transplanted KO/OEhiPSC-CM.
2024-12-10 | GSE279567 | GEO
Project description:The loss of compact myocardial cardiomyocyte (compact CM) identity suggests that PRDM16 deficiency may dramatically alter the cellular composition in left ventricular (LV) compact myocardium. To test this hypothesis, we performed single-cell RNA-seq (scRNA-seq) to examine gene dysreulation in Prdm16cKO heart. We also performed Visium Spatial Transcriptomics (ST) to facilitate mapping CM clusters to their original locations in the heart. As a result, we were able to demonstrate gene misregulation in Prdm16cKO mouse mainly occurred in LV compact CM.
2021-12-20 | GSE179392 | GEO