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論文
タイトル
タイトル(英)
Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies.
参照URL
https://researchmap.jp/YuichiroMiyaoka/published_papers/35727327
著者
著者(英)
Aidan M Fenix,Yuichiro Miyaoka,Alessandro Bertero,Steven M Blue,Matthew J Spindler,Kenneth K B Tan,Juan A Perez-Bermejo,Amanda H Chan,Steven J Mayerl,Trieu D Nguyen,Caitlin R Russell,Paweena P Lizarraga,Annie Truong,Po-Lin So,Aishwarya Kulkarni,Kashish Chetal,Shashank Sathe,Nathan J Sniadecki,Gene W Yeo,Charles E Murry,Bruce R Conklin,Nathan Salomonis
概要
概要(英)
Mutations in the cardiac splicing factor RBM20 lead to malignant dilated cardiomyopathy (DCM). To understand the mechanism of RBM20-associated DCM, we engineered isogenic iPSCs with DCM-associated missense mutations in RBM20 as well as RBM20 knockout (KO) iPSCs. iPSC-derived engineered heart tissues made from these cell lines recapitulate contractile dysfunction of RBM20-associated DCM and reveal greater dysfunction with missense mutations than KO. Analysis of RBM20 RNA binding by eCLIP reveals a gain-of-function preference of mutant RBM20 for 3' UTR sequences that are shared with amyotrophic lateral sclerosis (ALS) and processing-body associated RNA binding proteins (FUS, DDX6). Deep RNA sequencing reveals that the RBM20 R636S mutant has unique gene, splicing, polyadenylation and circular RNA defects that differ from RBM20 KO. Super-resolution microscopy verifies that mutant RBM20 maintains very limited nuclear localization potential; rather, the mutant protein associates with cytoplasmic processing bodies (DDX6) under basal conditions, and with stress granules (G3BP1) following acute stress. Taken together, our results highlight a pathogenic mechanism in cardiac disease through splicing-dependent and -independent pathways.
出版者・発行元
出版者・発行元(英)
誌名
誌名(英)
Nature communications
12
1
開始ページ
6324
終了ページ
6324
出版年月
2021年11月3日
査読の有無
招待の有無
掲載種別
研究論文(学術雑誌)
ISSN
DOI URL
https://doi.org/10.1038/s41467-021-26623-y
共同研究・競争的資金等の研究課題
研究者
宮岡 佑一郎 (ミヤオカ ユウイチロウ)