title: Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation.
abstract: Plant homeodomain finger protein 2 (PHF2), which contains a plant homeodomain and a Jumonji-C domain, is an epigenetic regulator that demethylates lysine 9 in histone 3 (H3K9me2). On the other hand, runt-related transcription factor 2 (Runx2) plays essential roles in bone development and regeneration. Given previous reports that the PHF2 mutation can cause dwarfism in mice and that PHF2 expression is correlated with that of Runx2 in differentiating thymocytes, we investigated whether PHF2 regulates Runx2-mediated bone formation. Overexpression of PHF2 facilitated bone development in newborn mice, and viral shRNA-mediated knockdown of PHF2 delayed calvarial bone regeneration in adult rats. In primary osteoblasts and C2C12 precursor cells, PHF2 enhances osteoblast differentiation by demethylating Runx2, while suppressor of variegation 3-9 homolog 1 (SUV39H1) inhibits bone formation by methylating it. The PHF2-Runx2 interaction is mediated by the Jumonji-C and Runt domains of the two proteins, respectively. The interaction between Runx2 and osteocalcin promoter is regulated by the methylation status of Runx2, i.e., the interaction is augmented when Runx2 is demethylated. Our results suggest that SUV39H1 and PHF2 reciprocally regulate osteoblast differentiation by modulating Runx2-driven transcription at the post-translational level. This study may provide a theoretical basis for the development of new therapeutic modalities for patients with impaired bone development or delayed fracture healing.
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: 1] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea [2] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea [3] Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.affiliation: 1] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea [2] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Kyoung-Hwa
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Haejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: 1] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea [2] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Uk-Il
authors.initials: UI
authors.lastname: Ju
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Seung Hyeok
authors.initials: SH
authors.lastname: Seok
authors.affiliation: Institute for Experimental Animals, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Seung Hyeon
authors.initials: SH
authors.lastname: Lim
authors.affiliation: Department of Cell and Developmental Biology, Seoul National University School of Dentistry, Seoul 110-749, Republic of Korea.
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.affiliation: Department of Cell and Developmental Biology, Seoul National University School of Dentistry, Seoul 110-749, Republic of Korea.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.affiliation: 1] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea [2] Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Yang-Sook
authors.initials: YS
authors.lastname: Chun
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism; D012886:Skull / Q000000981:diagnostic imaging / Q000502:physiology
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C493716:Runx2 protein, mouse; D015675:Osteocalcin; D056466:Histone Demethylases; C000598540:PHF2 protein, mouse; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases