Translational control by DHX36 binding to 5′UTR G-quadruplex is essential for muscle stem-cell regenerative functions

Xiaona Chen, Jie Yuan, Guang Xue, Silvia Campanario, Di Wang, Wen Wang, Xi Mou, Shiau Wei Liew, Mubarak Ishaq Umar, Joan Isern, Yu Zhao, Liangqiang He, Yuying Li, Christopher J. Mann, Xiaohua Yu, Lei Wang, Eusebio Perdiguero, Wei Chen, Yuanchao Xue, Yoshikuni Nagamine, Chun Kit Kwok, Hao Sun (), Pura Muñoz-Cánoves () and Huating Wang ()
Additional contact information
Xiaona Chen: Chinese University of Hong Kong
Jie Yuan: Chinese University of Hong Kong
Guang Xue: Chinese University of Hong Kong
Silvia Campanario: Universitat Pompeu Fabra (UPF), CIBERNED, ICREA
Di Wang: Chinese Academy of Sciences
Wen Wang: Southern University of Science and Technology
Xi Mou: City University of Hong Kong, Kowloon Tong
Shiau Wei Liew: City University of Hong Kong, Kowloon Tong
Mubarak Ishaq Umar: City University of Hong Kong, Kowloon Tong
Joan Isern: Universitat Pompeu Fabra (UPF), CIBERNED, ICREA
Yu Zhao: Chinese University of Hong Kong
Liangqiang He: Chinese University of Hong Kong
Yuying Li: Chinese University of Hong Kong
Christopher J. Mann: Universitat Pompeu Fabra (UPF), CIBERNED, ICREA
Xiaohua Yu: Chinese Academy of Sciences
Lei Wang: Chinese Academy of Sciences
Eusebio Perdiguero: Universitat Pompeu Fabra (UPF), CIBERNED, ICREA
Wei Chen: Southern University of Science and Technology
Yuanchao Xue: Chinese Academy of Sciences
Yoshikuni Nagamine: Novartis Research Foundation
Chun Kit Kwok: City University of Hong Kong, Kowloon Tong
Hao Sun: Chinese University of Hong Kong
Pura Muñoz-Cánoves: Universitat Pompeu Fabra (UPF), CIBERNED, ICREA
Huating Wang: Chinese University of Hong Kong

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: Abstract Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells (also called satellite cells, SCs). SCs are normally quiescent; when stimulated by damage, they activate and expand to form new fibers. The mechanisms underlying SC proliferative progression remain poorly understood. Here we show that DHX36, a helicase that unwinds RNA G-quadruplex (rG4) structures, is essential for muscle regeneration by regulating SC expansion. DHX36 (initially named RHAU) is barely expressed at quiescence but is highly induced during SC activation and proliferation. Inducible deletion of Dhx36 in adult SCs causes defective proliferation and muscle regeneration after damage. System-wide mapping in proliferating SCs reveals DHX36 binding predominantly to rG4 structures at various regions of mRNAs, while integrated polysome profiling shows that DHX36 promotes mRNA translation via 5′-untranslated region (UTR) rG4 binding. Furthermore, we demonstrate that DHX36 specifically regulates the translation of Gnai2 mRNA by unwinding its 5′ UTR rG4 structures and identify GNAI2 as a downstream effector of DHX36 for SC expansion. Altogether, our findings uncover DHX36 as an indispensable post-transcriptional regulator of SC function and muscle regeneration acting through binding and unwinding rG4 structures at 5′ UTR of target mRNAs.

Date: 2021
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DOI: 10.1038/s41467-021-25170-w

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