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Widespread translational control of fibrosis in the human heart by RNA-binding proteins

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Item Type:Article
Title:Widespread translational control of fibrosis in the human heart by RNA-binding proteins
Creators Name:Chothani, S. and Schäfer, S. and Adami, E. and Viswanathan, S. and Widjaja, A.A. and Langley, S.R. and Tan, J. and Wang, M. and Quaife, N.M. and Pua, C.J. and D'Agostino, G. and Shekeran, S.G. and George, B.L. and Lim, S. and Cao, E.Y. and van Heesch, S. and Witte, F. and Felkin, L.E. and Christodoulou, E.G. and Dong, J. and Blachut, S. and Patone, G. and Barton, P.J.R. and Hubner, N. and Cook, S.A. and Rackham, O.J.L.
Abstract: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 an 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.
Keywords:Dilated Cardiomyopathy, Fibrosis, Ribosome Profiling, RNA-Binding Proteins, TGF-beta1
Publisher:American Heart Association
Page Range:937-951
Date:10 September 2019
Official Publication:https://doi.org/10.1161/CIRCULATIONAHA.119.039596
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/17854/Preprint version

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