Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration

Yukino Hatazawa, Yusuke Ono, Yuma Hirose, Sayaka Kanai, Nobuharu L. Fujii, Shuichi Machida, Ichizo Nishino, Takahiko Shimizu, Masaki Okano, Yasutomi Kamei, Yoshihiro Ogawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1452-1467
Number of pages16
JournalFASEB Journal
Volume32
Issue number3
DOIs
Publication statusPublished - Mar 2018

Fingerprint

Growth Differentiation Factor 5
Muscle
Regeneration
Cell Differentiation
Skeletal Muscle
Satellites
Tissue Array Analysis
Sarcopenia
Azacitidine
Muscular Atrophy
Skeletal Muscle Fibers
DNA Methylation
Epigenomics
Knockout Mice
Methylation
Atrophy
Cell growth
Microarrays
Gene expression
Gene Expression

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration. / Hatazawa, Yukino; Ono, Yusuke; Hirose, Yuma; Kanai, Sayaka; Fujii, Nobuharu L.; Machida, Shuichi; Nishino, Ichizo; Shimizu, Takahiko; Okano, Masaki; Kamei, Yasutomi; Ogawa, Yoshihiro.

In: FASEB Journal, Vol. 32, No. 3, 03.2018, p. 1452-1467.

Research output: Contribution to journalArticle

Hatazawa, Y, Ono, Y, Hirose, Y, Kanai, S, Fujii, NL, Machida, S, Nishino, I, Shimizu, T, Okano, M, Kamei, Y & Ogawa, Y 2018, 'Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration', FASEB Journal, vol. 32, no. 3, pp. 1452-1467. https://doi.org/10.1096/fj.201700573R
Hatazawa, Yukino ; Ono, Yusuke ; Hirose, Yuma ; Kanai, Sayaka ; Fujii, Nobuharu L. ; Machida, Shuichi ; Nishino, Ichizo ; Shimizu, Takahiko ; Okano, Masaki ; Kamei, Yasutomi ; Ogawa, Yoshihiro. / Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration. In: FASEB Journal. 2018 ; Vol. 32, No. 3. pp. 1452-1467.
@article{5c8c49c50d964633bb53db64608594bf,
title = "Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration",
abstract = "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.",
author = "Yukino Hatazawa and Yusuke Ono and Yuma Hirose and Sayaka Kanai and Fujii, {Nobuharu L.} and Shuichi Machida and Ichizo Nishino and Takahiko Shimizu and Masaki Okano and Yasutomi Kamei and Yoshihiro Ogawa",
year = "2018",
month = "3",
doi = "10.1096/fj.201700573R",
language = "English",
volume = "32",
pages = "1452--1467",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "3",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85043594065&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043594065&partnerID=8YFLogxK

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 -