Malat1regulates myogenic differentiation and muscle regeneration through modulating MyoD transcriptional activity.
Malat1is one of the most abundant long non-coding RNAs in various cell types; its exact cellular function is still a matter of intense investigation. In this study we characterized the function ofMalat1in skeletal muscle cells and muscle regeneration. Utilizing bothin vitroandin vivoassays, we demonstrate thatMalat1has a role in regulating gene expression during myogenic differentiation of myoblast cells. Specifically, we found that knockdown ofMalat1accelerates the myogenic differentiation in cultured cells. Consistently,Malat1knockout mice display enhanced muscle regeneration after injury and deletion ofMalat1in dystrophic mdx mice also improves the muscle regeneration. Mechanistically, in the proliferating myoblasts,Malat1recruits Suv39h1 to MyoD-binding loci, causing trimethylation of histone 3 lysine 9 (H3K9me3), which suppresses the target gene expression. Upon differentiation, the pro-myogenic miR-181a is increased and targets the nuclearMalat1transcripts for degradation through Ago2-dependent nuclear RNA-induced silencing complex machinery; theMalat1decrease subsequently leads to the destabilization of Suv39h1/HP1β/HDAC1-repressive complex and displacement by a Set7-containing activating complex, which allows MyoD trans-activation to occur. Together, our findings identify a regulatory axis of miR-181a-Malat1-MyoD/Suv39h1 in myogenesis and uncover a previously unknown molecular mechanism ofMalat1action in gene regulation.
Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Xiaona
X
Chen
Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Liangqiang
L
He
Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Yu
Y
Zhao
Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Yuying
Y
Li
Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Suyang
S
Zhang
Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Kun
K
Sun
Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Karl
K
So
Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Fengyuan
F
Chen
Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Liang
L
Zhou
Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Leina
L
Lu
Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Lijun
L
Wang
Genome Regulation Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, China.
Xihua
X
Zhu
Genome Regulation Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, China.
Xichen
X
Bao
Genome Regulation Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou, China.
Miguel A
MA
Esteban
RNA Biology Laboratory, RIKEN Advanced Research Institute , Wako, Japan.
Shinichi
S
Nakagawa
Department of Cell and Developmental Biology, Chemical and Life Sciences Laboratory, University of Illinois at Urbana-Champaign , Urbana, IL, USA.
Kannanganattu V
KV
Prasanth
Division of Life Sciences, The Hong Kong University of Science and Technology , Hong Kong, China.
Zhenguo
Z
Wu
Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Hao
H
Sun
Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.
Huating
H
Wang
Malat1; MyoD; Suv39h1; miR-181; myogenesis