title: DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway.
abstract: Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation, but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated. During osteoclast differentiation, a shift toward more oxidative metabolic processes occurs. In this study we identified the de novo DNA methyltransferase 3a (Dnmt3a) as a transcription factor that couples these metabolic changes to osteoclast differentiation. We also found that receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclastogenesis, induces this metabolic shift towards oxidative metabolism, which is accompanied by an increase in S-adenosylmethionine (SAM) production. We found that SAM-mediated DNA methylation by Dnmt3a regulates osteoclastogenesis via epigenetic repression of anti-osteoclastogenic genes. The importance of Dnmt3a in bone homeostasis was underscored by the observations that Dnmt3a-deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast-specific deficiency in Dnmt3a have elevated bone mass due to a smaller number of osteoclasts. Furthermore, inhibition of DNA methylation by theaflavin-3,3'-digallate abrogated bone loss in models of osteoporosis. Thus, this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation, which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders.
authors.affiliation: 1] Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan. [2] WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan. [3] Japan Science and Technology Agency, CREST, Tokyo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Nishikawa
authors.affiliation: 1] Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan. [2] WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan. [3] Japan Science and Technology Agency, CREST, Tokyo, Japan. [4] Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Institute for Oral Science, Matsumoto Dental University, Nagano, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: 1] Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan. [2] Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.affiliation: Department of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shin-ichi
authors.identifier: 0000000291003885
authors.initials: S
authors.lastname: Kawaguchi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Tsujita
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Soma Central Hospital, Fukushima, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.affiliation: 1] Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan. [2] Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: 1] Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan. [2] Japan Science and Technology Agency, ERATO, Takayanagi Osteonetwork Project, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.affiliation: 1] Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan. [2] WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan. [3] Japan Science and Technology Agency, CREST, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
mesh_terms: D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology; D001862:Bone Resorption / Q000235:genetics*; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D015870:Gene Expression; D051379:Mice; D010010:Osteoclasts / Q000166:cytology*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D053245:RANK Ligand / Q000235:genetics* / Q000502:physiology; D012436:S-Adenosylmethionine / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D044946:Biflavonoids; C000715535:Dnmt3a protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; C585473:theaflavin-3,3'-digallate; D012436:S-Adenosylmethionine; D002392:Catechin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A