G3bp1-miR-1 axis regulates cardiomyocyte hypertrophy
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ABSTRACT:
PROVIDER: PRJNA764679 | ENA |
REPOSITORIES: ENA
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Project description:We examine the role of G3bp1, a RNA binding protein and site specific endoribonuclease in gene expression in isolated neonatal cardiomyocytes. RNAseq data from cardiomyocytes were infected with adenoviruses expressing shRNA against G3bp1 (ad-siG3bp1) or Luciferase (ad-siLUC, control) showed significant decrease in transcript abudnnace of cardiac-enriched genes involved in Calcium handling, contraction, action potential and sacromere function. On the other hand increase was observed in genes that regulate Hippo, TNF and TGFb signaling. Knockdown of G3bp1 inhibited endothelin-1 induced cardiomyocyte hypertrophy.
2022-01-14 | GSE184441 | GEO
Project description:Speckle-type POZ protein (SPOP), an E3 ubiquitin ligase, acts as a tumor suppressor. We identified G3BP1 as non-substrate interactor of SPOP. G3BP1 is a well-known oncogene in many cancer types, but its role in prostate cancer (PCa) remains largely elusive. We showed that G3BP1 functions as an upstream regulator and potent endogenous inhibitor of Cul3SPOP, suggesting a distinctive Cul3SPOP inactivation independent of SPOP mutations. Transcriptomic analysis together with functional studies revealed that the G3BP1-SPOP ubiquitin signaling axis is involved in PCa progression through activating AR signaling. Further, AR upregulates G3BP1 to potentiate feed-forward amplification of signaling through G3BP1-SPOP axis. Overall, we show G3BP1high PCa tumors constitute a new subset where G3BP1 inhibits Cul3SPOP function to upregulate AR signaling, and promotes tumorigenesis.
2021-09-26 | GSE138612 | GEO
Project description:Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.
2018-07-30 | GSE95140 | GEO
Project description:Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.
2018-07-30 | GSE95142 | GEO
Project description:Purpose: The physiological cardiac hypertrophy is an adaptive condition that does not associate with myocyte cell death while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. Alpha-2 macroglobulin (α-2M) an acute phase protein induces cardiac hypertrophy via the ERK1,2 and PI3K/Akt signaling. This study is aimed at exploring the miRNome of α-2M induced hypertrophied cardiomyocytes and to understand the role of miRNAs in determination of pathological and physiological hypertrophy. Methods: Hypertrophy was induced in H9c2 cardiomyoblasts using alpha-2 macroglobulin. The induction of hypertrophy is confirmed by microscopy and gene expression studies. Subsequently, the total RNA was isolated and small RNA sequencing was executed in Illumina HiSeq 2000. Results: Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy. Among the differentially expressed candidates, miR-99 family (miR-99a, miR-99b and miR-100) showed significant downregulation upon α-2M treatment while isoproterenol treatment (pathological hypertrophy) upregulated their expression. The binding site for Egr1 transcription factor was identified in the promoter region of miR-99 family, and interestingly all miRNAs with Egr1 binding site proven by ChIP-Seq were downregulated during physiological hypertrophy Conclusions: The results proved Egr-1 mediated regulation of miR-99 family determines the uniqueness of pathological and physiological hypertrophy. Upregulated miR-99 expression during pathological hypertrophy suggests that it can be a valuable diagnostic marker and potential therapeutic target for cardiac hypertrophy and heart failure. Small RNA profiles of control and hypertrophied cardiomyocyte H9c2 cells were generated by deep sequencing using Illumina HiSeq 2000
2015-11-01 | E-GEOD-73597 | biostudies-arrayexpress
Project description:Cardiomyocyte Transcriptomes in Cardiac Development and Hypertrophy
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Project description:Cmarr/miR-540-3p axis promotes cardiomyocyte maturation transition by orchestrating Dtna expression
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Project description:Downstream targets of uc.323-mediated cardiomyocyte hypertrophy
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Project description:Zinc dyshomeostasis has been involved in the pathogenesis of cardiac hypertrophy; however, the dynamic regulation of intracellular zinc and its downstream signaling in cardiac hypertrophy remain largely unknown. Here we screened ZIP (SLC39) family members that were responsible for zinc uptake in a phenylephrine (PE)-induced cardiomyocyte hypertrophy model. We found that Slc39a2 was the only member that was altered at mRNA level by PE treatment in neonatal rat ventricular myocytes (NRVMs), but its protein level was not affected. Zincpyr1 staining showed a significant decrease in zinc uptake after PE treatment or after Slc39a2 knockdown in NRVMs, indicating an inhibition of its transport activity during hypertrophy. Slc39a2 deficiency caused spontaneous hypertrophy in NRVMs, and further exacerbated the hypertrophic responses after PE treatment. RNA sequencing analysis confirmed a largely aggravated pro-hypertrophic transcriptome reprogramming after Slc39a2 knockdown. Interestingly, the innate immune pathways, including NOD signaling, TOLL-like receptor, NFB, and IRFs, were substantially enriched after Slc39a2 knockdown. Whereas IRF7, the most sensitive among all IRFs, did not mediate the effect of Slc39a2 in hypertrophy, pro-hypertrophy phosphorylations of NFB and STAT3 were significantly enhanced after Slc39a2 knockdown, in parallel with degradation of IkBα protein. Our data demonstrate that SLC39A2-mediated zinc homeostasis contributes to the remodeling of innate immune signaling in cardiomyocyte hypertrophy, and provide novel insights into the pathogenesis of heart failure and its treatment.
2021-11-24 | GSE175884 | GEO
Project description:Calcium signaling is a central regulator of cardiomyocyte growth and function. Calmodulin is a critical mediator of calcium signals. Because the amount of calmodulin within cardiomyocytes is limiting, precise regulation of calmodulin expression may be an important for regulation of calcium signaling. In this study, we show for the first time that calmodulin levels are regulated post-transcriptionally in heart failure. The cardiomyocyte-restricted microRNA miR-1 inhibited translation of calmodulin-encoding mRNAs via highly conserved target sites within their 3â-untranslated regions. In keeping with its effect on calmodulin expression, miR-1 downregulated calcium-calmodulin signaling through the calcineurin to NFAT. miR-1 also negatively regulated expression of Mef2a and Gata4, key transcription factors that mediate calcium-dependent changes in gene expression. Consistent with downregulation of these hypertrophy-associated genes, miR-1 attenuated cardiomyocyte hypertrophy in cultured neonatal rat cardiomyocytes and in the intact adult heart. Our data indicate that miR-1 regulates cardiomyocyte growth responses by negatively regulating the calcium-signaling components calmodulin, Mef2a, and Gata4. We show that miR-1 is downregulated in a murine heart failure model. miRNAs expression changes were measured in calcineurin transgenic model of heart failure and control mice using a Luminex platform. Reduced miR-1 expression was associated with broad alteration in expression of predicted target genes. To test this, we measured miRs including miR-1 and genome wide transcriptome changes in vivo and in vitro system. Calcineurin transgenic heart was compared to nontransgenic heart (NTg vs. CNTg). We also investigated the gene expression changes during the course of cardiomyocytes differentiation using DMSO treated P19CL6 cell lines. Two time points (day 6 and day 10) were compared to identified the gene expression changes of predicted miR-1 targets (Day 6 vs. Day 10).
2010-06-25 | E-GEOD-13874 | biostudies-arrayexpress