Hspa1a-regulated gene expression and alternative splicing in mouse cardiomyocytes are tightly related to cardiac hypertrophy
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ABSTRACT:
PROVIDER: PRJNA666077 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12727760_1.fastq.gz | Fastqsanger.gz | |||
| SRR12727760_2.fastq.gz | Fastqsanger.gz | |||
| SRR12727761_1.fastq.gz | Fastqsanger.gz | |||
| SRR12727761_2.fastq.gz | Fastqsanger.gz | |||
| SRR12727762_1.fastq.gz | Fastqsanger.gz |
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Project description:Regulatory factors play important roles in cardiac hypertrophy by regulating gene expression in cardiomyocytes.HSP70, a heat shock protein encoded by HSPA1A ,is induced by hypertrophic stimulation and then causes cardiac hypertrophy. However, the regulation mechanism of HSP70 in cardiac hypertrophy is unknown. In this study, we established the cardiac hypertrophy mouse model to explore the differentially expressed genes and found Hspa1a was significantly increased in treated samples. Then Hspa1a was overexpressed in mouse cardiac HL-1 cells and we analyzed the changes of transcriptome expression by high throughput sequencing. The results showed that HSPA1A selectively regulates the expression of ncRNAs (Rn7sk,Rmrp), negatively regulates the expression of genes involved in inflammatory and immune response, including Cxcl1，Ccl2，Ccl7,Cxcl5, Fas andC3, which were also validated by RT-qPCR experiment. The HSPA1A-regulated genes and ncRNAs are highly associated with cardiac hypertrophy. Alternative splicing analysis revealed HSPA1A preferred to regulate genes enriched in transcriptional regulation, including Asxl2 and Runx1. These results indicate that the heat shock protein-HSPA1A may play a role in the occurrence and development of myocardial hypertrophy by regulating the expression of immune inflammatory response related pathway genes and ncRNAs related to myocardial hypertrophy.
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Project description:Pathological cardiac hypertrophy can lead to heart failure and is one of the leading causes of death globally. Understanding the molecular mechanism of pathological cardiac hypertrophy will contribute to the treatment of heart failure. Deubiquitinating enzymes (DUBs) are essential to cardiac pathophysiology by precisely controlling protein function, localization, and degradation.This study set out to investigate the role of a DUB, USP25, in pathological cardiac hypertrophy, reveal its molecular mechanism, and hopefully provide a new therapeutic target for heart failure.We revealed increased protein level of USP25 expression in the cardiomyocytes in response to Ang II stimulation. USP25 deficiency aggravated cardiac hypertrophy and cardiac dysfunction under Ang II and TAC treatment. Mechanistically, LC-MS/MS analysis combined with Co-IP was used to identify SERCA2a, an anti-hypertrophy protein, as an interacting protein of USP25. Also, our data showed that USP25 bound to SERCA2a directly via its USP domain and cysteine at position 178 of USP25 exerts deubiquitination to maintain the stability of the SERCA2a protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining calcium content in cardiomyocytes. Moreover, restoration of USP25 expression via with AAV9 vectors in USP25-/- mice attenuated Ang II-induced cardiac hypertrophy and cardiac dysfunction, whereas SERCA2a myocardial overexpression could offset the effect of USP25.
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Project description:Cardiac hypertrophy is an independent risk factor for cardiovascular disease and heart failure. There is increasing evidence that microRNAs (miRNAs) play an important role in the regulation of messenger RNA (mRNA) and the pathogenesis of various cardiovascular diseases. However, the ability to comprehensively study cardiac hypertrophy on a gene regulatory level is impacted by the limited availability of human cardiomyocytes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer the opportunity for disease modeling. We utilized a previously established in vitro model of cardiac hypertrophy to interrogate the regulatory mechanism associated with the cardiac disease process. We performed miRNA sequencing and mRNA expression analysis on endothelin 1 (ET-1) stimulated hiPSC-CMs to describe associated RNA expression profiles. MicroRNA sequencing revealed over 250 known and 34 predicted novel miRNAs to be differentially expressed between ET-1stimulated and unstimulated control hiPSC-CMs. Messenger RNA expression analysis identified 731 probe sets with significant differential expression. Computational target prediction on significant differentially expressed miRNAs and mRNAs identified nearly 2000 target pairs. To characterize miRNA and mRNA expression patterns we utilized iCell Cardiomyocytes derived from human iPSCs (hiPSC-CMs). Based on preliminary dose-response and time-course studies, we stimulated these cells with ET-1 at 10-8M for 18h. We used unstimulated control (control-CM) and ET-1 stimulated (ET1-CM) hiPSCs from 3 separate experiments as triplicate data for this study. mRNA expression for the control-CM and ET1-CM samples was analyzed using GeneChip 3M-bM-^@M-^YIVT express arrays (Affymetrix).
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Project description:Cardiac hypertrophy is characterized by increase in the size of the cardiomyocytes which is initially triggered as an adaptive response due to various kinds of stimuli but ultimately becomes maladaptive with chronic exposure. Peroxisome proliferator activated receptor alpha (PPAR α), which is critical for mitochondrial biogenesis and fatty acid oxidation, is known to be down regulated in hypertrophied cardiomyocytes. The aim of the study was to unveil the role of PPAR α in the mechanism that drives myocardium towards maladaptation in chronic hypertrophy. Wild-type C57BL/6 and PPAR α-/- mice were subjected to isoproterenol treatment for 2 weeks (n=8). Proteomic analysis using Orbitrap mass spectrometer revealed an unexpected down regulation of apoptotic markers, Annexin V and p53. PPAR α regulated and non-regulated genes were validated using RT-PCR. Specificity for α isoform was confirmed using PPAR α agonist, fenofibrate and pan-agonist bezafibrate. Fenofibrate failed to restore PPAR α target genes, whereas bezafibrate managed to ameliorate the effects of isoproterenol for a subset of genes even in the absence of PPAR α. Autophagy markers like p62, Beclin1 and LC3 A/B were up regulated in PPAR α-/-mice therefore indicating an upsurge in autophagy. The results demonstrate hindrance to intrinsic apoptotic pathway and activation of autophagy in the absence of PPAR α in hypertrophic cardiomyocytes. Therefore, PPAR α signalling might act as a molecular switch between apoptosis and autophagy thereby playing a critical role in adaptive process in stress induced cardiomyocytes.
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