Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation
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ABSTRACT:
PROVIDER: PRJNA531914 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8877870_1.fastq.gz | Fastqsanger.gz | |||
| SRR8877870_2.fastq.gz | Fastqsanger.gz | |||
| SRR8877871_1.fastq.gz | Fastqsanger.gz | |||
| SRR8877871_2.fastq.gz | Fastqsanger.gz | |||
| SRR8877872_1.fastq.gz | Fastqsanger.gz |
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Project description:Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a series of microRNAs that induce cardiomyocyte proliferation and stimulate cardiac regeneration after myocardial infarction. Here we investigate the mechanism of action of the top ten most effective of these miRNAs. Analysis of the transcriptional profile of miRNA-treated cardiomyocytes revealed an involvement of the Hippo-YAP pathway in their action. All the investigated miRNAs activated YAP-mediated transcription, nuclear localization of active YAP and increased expression of YAP responsive genes. In particular, miR-199a-3p, one of the most effective miRNAs, directly downregulated two mRNA targets impinging on the Hippo pathway, the upstream inhibitory kinase TAOK1and the E3 ubiquitin ligase destroying YAP, b-TrCP. Most of the miRNAs that promoted proliferation also modulated the dynamics of the cardiomyocyte actin cytoskeleton. In particular, four miRNAs targeted Cofilin2 and increased the ratio between polymerized F-actin and monomeric G-actin. Cells treated with the most effective miRNAs (including miR-199a-3p) were round-shaped, with formation of gross bundles of actin fibers at the cytoplasm periphery. During mitosis, these miRNA-treated cardiomyocytes displayed disruption of the sarcomeric architecture. Downregulation of Cofilin2 itself was sufficient to promote cardiomyocyte proliferation, activate nuclear translocation of YAP and stimulate transcription of TEAD-responsive genes. Inhibition of F-actin polymerization decreased YAP activation. Collectively, these results indicate that activation of YAP and modulation of the acting cytoskeleton are major components of the pro-proliferative effect of miR-199a-3p and other miRNAs inducing cardiomyocyte proliferation
2019-04-11 | GSE129598 | GEO
Project description:Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase ?-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation.
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Project description:Neonatal mice adopt to pressure overload by inducing cardiomyocyte proliferation and angiogenesis
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Project description:Backgound: Cardiac pressure overload, for example in patients with aortic stenosis, induces irreversible damage in the myocardium leading to cardiac dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis. We therefore hypothesized that insufficient cardiac regeneration might contribute to the progression of pressure overload dependent disease. Here, we aimed to elucidate whether pressure overload in the regenerative stage shortly after birth could lead to a more adaptive cardiac response than in the non-regenerative stage in mice.nTAC in the non-regenerative stage induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, during induction of nTAC in the regenerative stage, cardiac function remained intact and this was associated with enhanced myocardial angiogenesis and innervation as well as increased cardiomyocyte proliferation, but neither hypertrophy nor fibrosis. Mechanistically, inhibition of cardiomyocyte proliferation and angiogenesis in nTAC in the regenerative phase by rapamycin triggered mortality and myocardial fibrosis, which both also similarly occurred upon inhibition of angiogenesis by PTK787, suggesting that both processes are essential for the adaptive cardiac response to nTAC. A comparative genome-wide transcriptomic analysis between hearts after nTAC in the regenerative versus the non-regenerative stage defined differentially expressed functional gene classes, and a related bioinformatics analysis suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response.tablished a new model of neonatal pressure-overload in mice, which when applied in the regenerative postnatal stage, triggers a purely adaptive myocardial response. Employing this model to identify new regulators might lead to novel therapeutic strategies to combat pressure overload induced myocardial disease.
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Project description:The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal (P) day 7. How to stimulate the adult cardiomyocyte to re-enter the cell cycle is still unknown. Accumulating evidence suggests that cardiomyocyte proliferation depends on its metabolic state. Due to the tight connection between the tricarboxylic acid cycle (TCA) and cell proliferation, we analyzed the TCA metabolites between P0.5 and P7 mouse hearts and found that α-ketoglutarate (α-KG) ranked first among the decreased metabolites. The intraperitoneal injection of exogenous α-KG extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction (MI) by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-KG levels. Mechanistically, α-KG activates Jmjd3, a histone lysine demethylase, that decreases H3K27me3 expression and deposition of H3K4me3 at the promoters of cell cycle and structural maturation genes in cardiomyocytes. Our present study shows that α-KG promotes cardiomyocyte proliferation by Jmjd3-dependent demethylation and inactivation of H3K27me3 andH3K4me3, which is a potential therapeutic approach for treating MI and heart failure.
2024-07-12 | GSE272104 | GEO
Project description:The adult mammalian heart has little regenerative capacity after myocardial infarction (MI) while neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI. Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and non-coding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two thirds of each of the mRNAs, lncRNAs and microRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these microRNAs, miR-144-3p, miR-195a-5p, miR-451a and miR-6240 showed evidence of functional conservation in human cardiomyocytes. The sets of mRNAs, miRNAs and lncRNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.
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