Translational control of cardiac fibrosis (I)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA507253 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8249100.fastq.gz | Fastqsanger.gz | |||
| SRR8249110.fastq.gz | Fastqsanger.gz | |||
| SRR8249120_1.fastq.gz | Fastqsanger.gz | |||
| SRR8249120_2.fastq.gz | Fastqsanger.gz | |||
| SRR8249130_1.fastq.gz | Fastqsanger.gz |
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Project description:Translational control of cardiac fibrosis
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Project description:Translational control of cardiac fibrosis (II)
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Project description:Background: Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global post-transcriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. Methods: Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used a RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. The integration with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients demonstrates that these post-transcriptional mechanisms are also active in the diseased fibrotic human heart. Results: We generated nucleotide-resolution translatome data during the TGFβ1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in post-transcriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested the same post-transcriptional regulatory network was underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as PUM2 and QKI that work in concert to regulate the translation of target transcripts in human diseased hearts. Furthermore, silencing of both PUM2 and QKI inhibits the transition of fibroblasts toward pro-fibrotic myofibroblasts in response to TGFβ1. Conclusions: We reveal widespread translational effects of TGFβ1 and define novel post-transcriptional regulatory networks that control the fibroblast-to-myofibroblast transition. These networks are active in human heart disease and silencing of hub genes limits fibroblast activation. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure.
2019-10-03 | GSE131111 | GEO
Project description:Cardiac fibroblasts from 4 patients treated for up to 24 hours with TGFB1
2019-10-03 | GSE123018 | GEO
Project description:Heart failure is one of the leading causes of death and it often accompanies activation of quiescent cardiac myofibroblasts, which results in cardiac fibrosis and resulting cardiac remodeling. Circular RNA, one form of non-coding RNA discovered recently, is formed by backsplicing of 3’ end to 5’ end of exons and is known to be closely related to the variety of pathophysiological function as well as normal homeostasis. However, its roles in the cardiovascular diseases, especially in cardiac fibrosis, are not fully studied. Circular RNAs (circRNAs) are formed by backsplicing events of 3′ end to 5′ end. To identify circRNA candidates, RNA sequencing (RNA-seq) datasets were obtained from transverse aortic constriction (TAC)-induced hearts. Especially, we were interested in cardiac fibroblast-specific circRNAs that affect its differentiation and cardiac fibrosis. Thus, in the present study, by utilizing RNA sequencing analysis followed by diverse bioinformatic or biochemical studies, we identified and characterized circRNA that may affect the pathologic remodeling of heart.
2023-12-14 | GSE240332 | GEO
Project description:Loss of m6A methyltransferase METTL5 promotes cardiac hypertrophy through translational control of SUZ12
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Project description:Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in rheumatic disease systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Fos-related antigen-2 (Fosl-2) has been implicated in development of organ fibrosis. Mice overexpressing Fosl-2 (Fosl-2tg) showed interstitial cardiac fibrosis, disorganized connexin43/40 in intercalated discs and deregulated expression of genes controlling conduction system. Fosl-2tg mice developed higher heart rate (HR), prolonged QT intervals, arrhythmias with prevalence of premature ventricular contractions, ventricular tachycardias, II-degree atrio-ventricular blocks and reduced HR variability. Following stimulation with isoproterenol Fosl-2tg mice showed impaired HR response. To assess the role of inflammation in cardiac fibrosis we used Rag2-/-Fosl-2tg mice lacking T/B cells. These mice showed no myocardial fibrosis and ECG abnormalities. Transcriptomics analysis of cardiac Rag-2-/-Fosl-2wt/Rag2-/-Fosl-2tg/Fosl-2tg fibroblasts revealed that systemic inflammation triggered fibrotic and arrhythmogenic alterations while Fosl-2-overexpression mediated profibrotic signature. In human cardiac fibroblasts FOSL-2-overexpression enhanced myofibroblast signature under proinflammatory or profibrotic stimuli. These results demonstrate that under immunofibrotic conditions activator protein 1 transcription factor component Fosl-2 exaggerates myocardial fibrosis, arrhythmias and aberrant response to stress.
2022-10-27 | E-MTAB-12271 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-10-03 | GSE131112 | GEO
Project description:Conversion of cardiospheres derived primitive cardiac stromal cells into myofibroblasts is typically associated with hypoxia conditions, metabolic insults, and/or inflammation, all of which are predisposing factors to cardiac fibrosis and heart failure. We hypothesized that this conversion could be also mediated by response of these cells to mechanical cues through activation of the Hippo transcriptional pathway. The objective of the present study was to assess the role of cellular/nuclear straining forces acting in myofibroblast differentiation of cardiospheres derived primitive cardiac stromal cells under the control of YAP transcription factor and to validate this finding using a pharmacological agent that interferes with the interactions of the YAP/TAZ complex with their cognate transcription factors TEADs, under high-strain and pro-fibrotic stimulation. We employed high content imaging, 2D/3D culture, atomic force microscopy mapping and molecular methods to prove the role of cell/nuclear straining in YAP-dependent fibrotic programming in a mouse model of ischemia-dependent cardiac fibrosis and in human-derived primitive cardiospheres derived primitive cardiac stromal cells . We also tested treatment of cells with Verteporfin, a drug known to prevent the association of the YAP/TAZ complex with their cognate transcription factors TEADs. Results suggested that pharmacologically targeting the YAP-dependent pathway overrides the pro-fibrotic activation of cardiospheres derived primitive cardiac stromal cells by mechanical cues in vitro, and that this occurs even in the presence of pro-fibrotic signaling mediated by TGF-β1. In vivo administration of Verteporfin in mice with permanent cardiac ischemia reduced significantly fibrosis and morphometric remodeling but did not improve cardiac performance. Our study indicates that preventing molecular translation of mechanical cues in cardiospheres derived primitive cardiac stromal cells reduces the impact of cardiac maladaptive remodeling with a positive effect on fibrosis.
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Project description:Translational control of breast cancer plasticity
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