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EIF4G2-dependent translation of pro-fibrotic mRNAs is essential for cardiac fibroblast activation (RIP-Seq)

ABSTRACT: RNA-binding proteins control gene expression in cardiac fibroblasts during TGFb-driven fibrotic responses, including the eukaryotic translation initiation factor 4G2 (eIF4G2), which was known to facilitate alternative mRNA translation during cellular stresses. However, the precise role of eIF4G2 in cardiac fibroblast activation in response to fibrotic stress remains unclear. In this study, we found increased eIF4G2 protein levels in the hearts of heart failure patients and myocardial infarcted mice, as well as in TGFb-treated immortalized human and primary mouse cardiac fibroblasts. Depletion of eIF4G2 led to predominant translational downregulation of genes that are enriched in focal adhesion and extracellular matrix pathways. eIF4G2 knockdown reduced the proliferation, migration, and collagen secretion of TGFb-treated cardiac fibroblasts. Mechanistically, we found that the translation of IGFBP7 mRNA relies on eIF4G2, which is crucial for ECM production in response to pro-fibrotic stimuli. The interaction between eIF4G2 and a DEAD box RNA helicase DDX24 can regulate IGFBP7 protein expression in cardiac fibroblasts. Together, these findings suggest that the TGFb-eIF4G2-IGFBP7 axis establishes a novel translational regulatory circuit that governs cardiac fibroblast activation. Furthermore, conditional knockout of Eif4g2 in POSTN-positive myofibroblasts reduced cardiac fibrosis in the myocardial infarction mouse model, thus improving cardiac function. Our study provides insights into the molecular mechanism of eIF4G2-mediated translational regulation of crucial physiological mRNAs during cardiac fibroblast activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239824 | GEO | 2024/07/31

REPOSITORIES: GEO

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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.

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EIF4G2-dependent translation of pro-fibrotic mRNAs is essential for cardiac fibroblast activation (RIP-Seq)

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