title: Dnmt3a Regulates Proliferation of Muscle Satellite Cells via p57Kip2.
abstract: Cell differentiation status is defined by the gene expression profile, which is coordinately controlled by epigenetic mechanisms. Cell type-specific DNA methylation patterns are established by chromatin modifiers including de novo DNA methyltransferases, such as Dnmt3a and Dnmt3b. Since the discovery of the myogenic master gene MyoD, myogenic differentiation has been utilized as a model system to study tissue differentiation. Although knowledge about myogenic gene networks is accumulating, there is only a limited understanding of how DNA methylation controls the myogenic gene program. With an aim to elucidate the role of DNA methylation in muscle development and regeneration, we investigate the consequences of mutating Dnmt3a in muscle precursor cells in mice. Pax3 promoter-driven Dnmt3a-conditional knockout (cKO) mice exhibit decreased organ mass in the skeletal muscles, and attenuated regeneration after cardiotoxin-induced muscle injury. In addition, Dnmt3a-null satellite cells (SCs) exhibit a striking loss of proliferation in culture. Transcriptome analysis reveals dysregulated expression of p57Kip2, a member of the Cip/Kip family of cyclin-dependent kinase inhibitors (CDKIs), in the Dnmt3a-KO SCs. Moreover, RNAi-mediated depletion of p57Kip2 replenishes the proliferation activity of the SCs, thus establishing a role for the Dnmt3a-p57Kip2 axis in the regulation of SC proliferation. Consistent with these findings, Dnmt3a-cKO muscles exhibit fewer Pax7+ SCs, which show increased expression of p57Kip2 protein. Thus, Dnmt3a is found to maintain muscle homeostasis by epigenetically regulating the proliferation of SCs through p57Kip2.
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo, Japan.|Department of Orthopaedic Surgery, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Naito
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo, Japan.|Department of Systems BioMedicine, National Center for Child Health and Development, Setagaya-Ku, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Systems BioMedicine, National Center for Child Health and Development, Setagaya-Ku, Tokyo, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Inagawa
authors.affiliation: Department of Systems BioMedicine, National Center for Child Health and Development, Setagaya-Ku, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Regenerative Medicine, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Morioka, Oobu, Aichi, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Orthopaedic Surgery, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo, Japan.|Department of Systems BioMedicine, National Center for Child Health and Development, Setagaya-Ku, Tokyo, Japan.|Japan Agency for Medical Research and Development, the Core Research for the Evolutionary Science and Technology, Chiyoda-ku, Tokyo, Japan.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asahara
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000378:metabolism*; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012038:Regeneration; D014057:Tomography, X-Ray Computed
chemical_list: C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; C000715535:Dnmt3a protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A