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Translational control of cardiac fibrosis

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Item Type:Preprint
Title:Translational control of cardiac fibrosis
Creators Name:Chothani, S. and Schafer, S. and Adami, E. and Viswanathan, S. and Widjaja, A.A. and Langley, S.R. and Tan, J. and Chee, J.P. and D'Agostino, G. 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 miRNA- and RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. To reveal post-transcriptional mechanisms in the human fibrotic heart, we then integrated our findings with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients. 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 an extensive post-transcriptional regulatory network 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. Conclusions: We reveal widespread translational effects of TGFβ1 and define novel post-transcriptional events that control the fibroblast-to-myofibroblast transition. Regulatory networks that affect ribosome occupancy in fibroblasts are paralleled in human heart disease. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:451666
Date:24 October 2018
Official Publication:https://doi.org/10.1101/451666
Related to:
https://edoc.mdc-berlin.de/18325/Preprint version

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