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

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• dc.contributor.author Chen, Xiaona
• dc.contributor.author Muñoz Cánoves, Pura, 1962-
• dc.contributor.author Wang, Huating
• dc.date.accessioned 2021-10-06T06:57:03Z
• dc.date.available 2021-10-06T06:57:03Z
• dc.date.issued 2021
• dc.description.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.
• dc.description.sponsorship This work was supported by General Research Funds (GRF) from the Research Grants Council (RGC) of the Hong Kong Special Administrative Region (14115319, 14100018, 14100620, 14106117 and 14106521 to H.W.; 14120420, 14116918, and 14120619 to H.S.); Guangdong Natural Science Foundation from Guangdong Basic and Applied Basic Research Foundation to X.C. (Project code: 2019A1515010670); the National Natural Science Foundation of China (NSFC) to H.W. (Project code: 31871304); Collaborative Research Fund (CRF) from RGC to H.W. (C6018-19GF); CUHK Direct Grant for Research to H.W. (Project code: 4054482); NSFC/RGC Joint Research Scheme to H.S. (Project code: N_CUHK 413/18); Hong Kong Epigenomics Project (EpiHK) Fund to H.W. and H.S.; Area of Excellence Scheme (AoE) from RGC (Project number: AoE/M-402/20). Work in PMC laboratory was supported by Spanish Ministry of Science, Innovation and Universities, Spain (grants RTI2018-096068-B-I00 and SAF 2015-70270-REDT, a María de Maeztu Unit of Excellence award to UPF [MDM-2014-0370], and a Severo Ochoa Center of Excellence award to the CNIC [SEV-2015-0505]), ERC-2016-AdG-741966, La Caixa-HEALTH (HR17-00040), MDA, UPGRADE-H2020-825825, AFM and DPP-E. S.C. is recipient of a FI fellowship from AGAUR. Work in CKK laboratory was supported by Shenzhen Basic Research Project (JCYJ20180507181642811), Research Grants Council of the Hong Kong SAR (CityU 11101519, CityU 11100218, N_CityU110/17, CityU 21302317), Croucher Foundation Project (9509003, 9500030), State Key Laboratory of Marine Pollution Director Discretionary Fund, City University of Hong Kong projects (6000711, 7005503, 9680261, and 9667222 to C.K.K.). Work in YX laboratory was supported by the National Natural Science Foundation of China (32025008 and 91940306 to Y.X.).
• dc.format.mimetype application/pdf
• dc.identifier.citation Chen X, Yuan J, Xue G, Campanario S, Wang D, Wang W et al. Translational control by DHX36 binding to 5'UTR G-quadruplex is essential for muscle stem-cell regenerative functions. Nat Commun. 2021;12(1):5043. DOI: 10.1038/s41467-021-25170-w
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-021-25170-w
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/48574
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2021;12(1):5043
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/741966
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825825
• dc.rights © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cell biology
• dc.subject.keyword Muscle stem cells
• dc.subject.keyword Regeneration
• dc.subject.keyword Stem-cell research
• dc.subject.keyword Translation
• dc.title Translational control by DHX36 binding to 5'UTR G-quadruplex is essential for muscle stem-cell regenerative functions
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion