TEAD-independent mechanisms of YAP function in cardiomyocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315945 | GEO | 2026/01/20
REPOSITORIES: GEO
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Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.
2022-02-15 | PXD011791 | Pride
Project description:The regenerative capacity of the adult mammalian heart is constrained by the post-mitotic nature of cardiomyocytes (CMs). Conversely, neonatal mouse hearts exhibit a regenerative window within the first week of life. Here, we demonstrate that an injury-induced Clusterin-positive (Clu+) CM population reprograms macrophages, facilitating heart regeneration during this timeframe. Clu+ CMs are selectively induced in the border zone of regenerative hearts across multiple species, contrasting with their absence in non-regenerative hearts. Genetic ablation of Clu+ CMs or Clu impedes neonatal heart regeneration, while transplantation of engineered human organoids enriched in Clu+ CMs or Clu overexpression promotes myocardial regeneration in adult mice. Mechanistically, Clu+ CMs secrete CLU, binding to TLR4 in macrophages, directing them toward an immune-suppressive neonatal-like phenotype through Cpt1a-mediated metabolic reprogramming, inducing BMP2 and promoting CM proliferation. Our findings unveil a novel cellular source for mammalian heart regeneration and highlight the fundamental roles of cardio-immune interaction in cardiac repair.
2025-11-24 | GSE254056 | GEO
Project description:The regenerative capacity of the adult mammalian heart is constrained by the post-mitotic nature of cardiomyocytes (CMs). Conversely, neonatal mouse hearts exhibit a regenerative window within the first week of life. Here, we demonstrate that an injury-induced Clusterin-positive (Clu+) CM population reprograms macrophages, facilitating heart regeneration during this timeframe. Clu+ CMs are selectively induced in the border zone of regenerative hearts across multiple species, contrasting with their absence in non-regenerative hearts. Genetic ablation of Clu+ CMs or Clu impedes neonatal heart regeneration, while transplantation of engineered human organoids enriched in Clu+ CMs or Clu overexpression promotes myocardial regeneration in adult mice. Mechanistically, Clu+ CMs secrete CLU, binding to TLR4 in macrophages, directing them toward an immune-suppressive neonatal-like phenotype through Cpt1a-mediated metabolic reprogramming, inducing BMP2 and promoting CM proliferation. Our findings unveil a novel cellular source for mammalian heart regeneration and highlight the fundamental roles of cardio-immune interaction in cardiac repair.
2025-11-24 | GSE254055 | GEO
Project description:The regenerative capacity of the adult mammalian heart is constrained by the post-mitotic nature of cardiomyocytes (CMs). Conversely, neonatal mouse hearts exhibit a regenerative window within the first week of life. Here, we demonstrate that an injury-induced Clusterin-positive (Clu+) CM population reprograms macrophages, facilitating heart regeneration during this timeframe. Clu+ CMs are selectively induced in the border zone of regenerative hearts across multiple species, contrasting with their absence in non-regenerative hearts. Genetic ablation of Clu+ CMs or Clu impedes neonatal heart regeneration, while transplantation of engineered human organoids enriched in Clu+ CMs or Clu overexpression promotes myocardial regeneration in adult mice. Mechanistically, Clu+ CMs secrete CLU, binding to TLR4 in macrophages, directing them toward an immune-suppressive neonatal-like phenotype through Cpt1a-mediated metabolic reprogramming, inducing BMP2 and promoting CM proliferation. Our findings unveil a novel cellular source for mammalian heart regeneration and highlight the fundamental roles of cardio-immune interaction in cardiac repair.
2025-11-24 | GSE253859 | GEO
Project description:YAP1 (Yes-associated protein 1) is transcriptional co-activator that partners with the TEAD family of transcription factors to regulate gene expression. Increased YAP-TEAD activity is strongly implicated in the development, progression, and metastasis of several cancer types including melanoma, but the YAP-TEAD target genes that are responsible for YAP-TEAD-dependent melanoma progression and metastasis are largely unknown. To identify YAP-TEAD regulated genes in metastatic melanoma cells we used RNA-sequencing to compare gene expression in control A375 human melanoma cells to A375 cells expressing mutant forms of YAP with increased transcriptional activity due to the mutation of LATS inhibitory phosphorylation sites (YAPS127A or YAPS127A,S381A). To determine which YAP-dependent gene expression changes are mediated by TEADs we also included a mutant form of YAP that is unable to bind TEADS (YAPS94A,S127A).
2024-03-29 | GSE234083 | GEO
Project description:Cardiomyocytes exhibit differential growth patterns throughout development. In fetal life the increase in cardiac mass is associated with hyperplastic growth and cardiomyocyte proliferation. The majority of fetal cardiomyocytes are also mononucleated. During the early neonatal period in mice there is a switch from hyperplastic to hypertrophic growth of cardiomyocytes. This period is characterized by bi-nucleation and polyploidization of cardiomyocyte nuclei and a decreased capacity for cardiomyocytes to proliferate and complete cytokinesis. Increases in myocardial mass occur predominantly via hypertrophic growth. Adult mammalian cardiomyocytes are generally accepted to have little or no proliferative capacity and to be terminally withdrawn from the cell cycle. The vast majority of adult murine cardiomyocytes are bi-nucleated. The present study sought to accurately establish the growth pattern of cardiomyocytes throughout development in mice and identify genes associated with the switch from hyperplastic to hypertrophic growth. These cell cycle associated genes are crucial to the understanding of the mechanisms of bi-nucleation, polyploidization and hypertrophy in the neonatal period. Cardiomyocytes were FACS sorted from the hearts of ED11-12 embryos, neonatal day 3-4 and adult (10 week) eGFP ?-MHC mice whereby GFP expression is driven constitutively by the ?-MHC promoter. Gene analyses identified genes whose expression was predicted to be particular to day 3 -4 neonatal cardiomyocytes, compared to embryonic or adult cells. Cell cycle associated genes are crucial to the understanding of the mechanisms of bi-nucleation and hypertrophy in the neonatal period, and offer attractive candidates for manipulation. Total RNA obtained from isolated cardiomyocytes from ED11-12; Neonatal day 3-4 and adult timepoints compared with each other. Several hearts per sample, RNA was pooled within samples. FACS samples were prepared in the following manner: embryonic, neonatal and adult hearts were dissected and dissociated to single cell solution with Liberase Blendzyme 3 (0.1 mg/ml) (Roche Diagnostics), washed and spun down and resuspended in cardiomyocyte isolation buffer (130 mM NaCl; 5 mM KCl; 1.2 mM KH2PO4; 6 mM HEPES; 5 mM NaHCO3; 1 mM MgCl2; 5 mM Glucose).
2010-06-24 | E-GEOD-17020 | biostudies-arrayexpress
Project description:TEAD transcription factors are responsible for the transcriptional output of Hippo signalling1,2. TEAD activity is primarily regulated by phosphorylation of its coactivators YAP and TAZ3,4. In addition, cysteine palmitoylation has recently been shown to regulate TEAD activity5,6. Here, we report lysine long-chain fatty acylation as a novel posttranslational modification of TEADs. Lysine fatty acylation occurs spontaneously via intramolecular transfer of acyl groups from the proximal acylated cysteine residue. Lysine fatty acylation, like cysteine palmitoylation, contributes to the transcriptional activity of TEADs by enhancing the interaction with YAP and TAZ, but it is more stable than cysteine acylation, suggesting that the lysine fatty-acylated TEAD acts as a “stable active form”. Significantly, lysine fatty acylation of TEAD increased upon Hippo signalling activation, despite a decrease in cysteine acylation. Our results provide new insight into the role of fatty acyl modifications in the regulation of TEAD activity.
2023-03-19 | PXD033939 | Pride
Project description:YAP transcriptional regulator controls cell mechanics by activating genes involved in cell-matrix interaction following extracellular matrix (ECM) remodelling and stiffening. YAP is needed for cardiogenesis in mouse but is repressed in adult cardiomyocytes. The protein is reactivated following ischemic insults, although the timing and mechanisms underlying YAP depletion during heart development and the reason for its reactivation are unclear. Here, we combine pluripotent stem cell (PSC) cardiac differentiation, mouse embryo development and human heart tissue analysis to demonstrate that the fine-tuning of cell mechanics, as controlled by YAP multiphasic activation through TEAD transcription, is crucial for mesoderm commitment and cardiac progenitor specification. Finally, by adopting induced PSC models of dilated cardiomyopathy, we prove that YAP-TEAD reactivation in diseased cardiomyocytes empowers calcium handling apparatus and increases cell contractility. Given YAP prompt activation following myocardial infarction, we unveil a novel role for mechanosensing in connecting ECM remodelling to cardiomyocyte function in pathological heart.
2020-10-30 | E-MTAB-7619 | biostudies-arrayexpress
Project description:YAP transcriptional regulator controls cell mechanics by activating genes involved in cell-matrix interaction following extracellular matrix (ECM) remodelling and stiffening. YAP is needed for cardiogenesis in mouse but is repressed in adult cardiomyocytes. The protein is reactivated following ischemic insults, although the timing and mechanisms underlying YAP depletion during heart development and the reason for its reactivation are unclear. Here, we combine pluripotent stem cell (PSC) cardiac differentiation, mouse embryo development and human heart tissue analysis to demonstrate that the fine-tuning of cell mechanics, as controlled by YAP multiphasic activation through TEAD transcription, is crucial for mesoderm commitment and cardiac progenitor specification. Finally, by adopting induced PSC models of dilated cardiomyopathy, we prove that YAP-TEAD reactivation in diseased cardiomyocytes empowers calcium handling apparatus and increases cell contractility. Given YAP prompt activation following myocardial infarction, we unveil a novel role for mechanosensing in connecting ECM remodelling to cardiomyocyte function in pathological heart.
2020-10-30 | E-MTAB-7620 | biostudies-arrayexpress
Project description:The regenerative capacity of the mammalian heart is lost quickly after birth when cardiomyocytes stop dividing and undergo cell cycle arrest. Thus, the adult mammalian heart lacks the ability to heal itself to any appreciable amount after ischemic injury such as myocardial infarction. Heart growth begins during fetal life with the first phase of DNA synthesis that is exclusively associated with cardiomyocyte proliferation. This process proceeds until 12 hours after birth and is defined as 0 days in our submitted samples. Cardiomyocytes division is undetectable at neonatal day 1. To analyze the molecular mechanisms responsible for cessation of cardiomyocyte proliferation, we performed genome-wide miRNA microarray profiling by comparing postnatal days 0 vs 1d.This revealed a profile of 8 significantly downregulated miRNAs in the proliferative DKO hearts (versus vehicle-injected control), that were enriched for mRNA targets involved in cell cycle regulation. In vitro studies have demonstrated that knockdown of these 8 miRNAs in neonatal rat cardiomyocytes can increase the occurrence of cytokinetic events. Ultimately, we aim to inject antagomirs targeting these miRNAs into mice post-myocardial infarction to determine the effect of these miRNAs on heart function and cardiomyocyte proliferation in vivo.
2022-01-30 | E-MTAB-9256 | biostudies-arrayexpress