TY - JOUR
T1 - Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration
AU - Hatazawa, Yukino
AU - Ono, Yusuke
AU - Hirose, Yuma
AU - Kanai, Sayaka
AU - Fujii, Nobuharu L.
AU - Machida, Shuichi
AU - Nishino, Ichizo
AU - Shimizu, Takahiko
AU - Okano, Masaki
AU - Kamei, Yasutomi
AU - Ogawa, Yoshihiro
N1 - Funding Information:
Microarray data analysis was in part performed at the Medical Research Support Center, Graduate School of Medicine, Kyoto University. This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT), and by the Council for Science, Technology, and Innovation (CSTI), Cross-Ministerial Strategic Innovation Promotion Program (SIP), and Technologies for Creating Next-Generation Agriculture, Forestry, and Fisheries (funding agency: Bio-oriented Technology Research Advancement Institution; NARO). This study was also supported in part by the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kuma-moto University. The funders had no role in the study design, data collection and analysis, decision to publish, and preparation of the article. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2018/3
Y1 - 2018/3
N2 - DNAmethylation is an epigenetic mechanism regulating gene expression. In this study, we observed that DNAmethyltransferase 3a (Dnmt3a) expression is decreased after muscle atrophy.Wemade skeletalmuscle-specific Dnmt3a-knockout (Dnmt3a-KO) mice. The regeneration capacity after muscle injury was markedly decreased in Dnmt3a-KOmice.DiminishedmRNAand protein expression of Dnmt3awere observed in skeletalmuscles aswell as in satellite cells, which are important formuscle regeneration, in Dnmt3a-KOmice. Dnmt3a-KO satellite cell showed smaller in size (length/area), suggesting suppressed myotube differentiation. Microarray analysis of satellite cells showed that expression of growth differentiation factor 5 (Gdf5)mRNAwasmarkedly increased in Dnmt3a-KOmice. TheDNA methylation level of the Gdf5 promoter wasmarkedly decreased in Dnmt3a-KO satellite cells. In addition, DNA methylation inhibitor azacytidine treatment increased Gdf5 expression in wild-type satellite cells, suggesting Gdf5 expression is regulated byDNAmethylation. Also, we observed increased inhibitor of differentiation (a target of Gdf5)mRNA expression in Dnmt3a-KO satellite cells. Thus, Dnmt3a appears to regulate satellite cell differentiation viaDNAmethylation. Thismechanism may play a role in the decreased regeneration capacity during atrophy such as in aged sarcopenia.
AB - DNAmethylation is an epigenetic mechanism regulating gene expression. In this study, we observed that DNAmethyltransferase 3a (Dnmt3a) expression is decreased after muscle atrophy.Wemade skeletalmuscle-specific Dnmt3a-knockout (Dnmt3a-KO) mice. The regeneration capacity after muscle injury was markedly decreased in Dnmt3a-KOmice.DiminishedmRNAand protein expression of Dnmt3awere observed in skeletalmuscles aswell as in satellite cells, which are important formuscle regeneration, in Dnmt3a-KOmice. Dnmt3a-KO satellite cell showed smaller in size (length/area), suggesting suppressed myotube differentiation. Microarray analysis of satellite cells showed that expression of growth differentiation factor 5 (Gdf5)mRNAwasmarkedly increased in Dnmt3a-KOmice. TheDNA methylation level of the Gdf5 promoter wasmarkedly decreased in Dnmt3a-KO satellite cells. In addition, DNA methylation inhibitor azacytidine treatment increased Gdf5 expression in wild-type satellite cells, suggesting Gdf5 expression is regulated byDNAmethylation. Also, we observed increased inhibitor of differentiation (a target of Gdf5)mRNA expression in Dnmt3a-KO satellite cells. Thus, Dnmt3a appears to regulate satellite cell differentiation viaDNAmethylation. Thismechanism may play a role in the decreased regeneration capacity during atrophy such as in aged sarcopenia.
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U2 - 10.1096/fj.201700573R
DO - 10.1096/fj.201700573R
M3 - Article
C2 - 29146735
AN - SCOPUS:85043594065
VL - 32
SP - 1452
EP - 1467
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 3
ER -