title: EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy.
abstract: Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. The decrease in chondrocyte proliferation is due in part to derepression of cyclin-dependent kinase inhibitors Ink4a/b, while ineffective chondrocyte hypertrophy is due to the suppression of IGF signalling by the increased expression of IGF-binding proteins. Collectively, our findings reveal a critical role for H3K27 methylation in the regulation of chondrocyte proliferation and hypertrophy in the growth plate, which are the central determinants of skeletal growth.
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Lui
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA.
authors.forename: Presley
authors.initials: P
authors.lastname: Garrison
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA.
authors.forename: Quang
authors.initials: Q
authors.lastname: Nguyen
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Ad
authors.affiliation: Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg8, Room 1A11, 8 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Chithra
authors.initials: C
authors.lastname: Keembiyehetty
authors.affiliation: Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg8, Room 1A11, 8 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Chen
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA.
authors.forename: Youn Hee
authors.initials: YH
authors.lastname: Jee
authors.affiliation: Division of Pediatric Endocrinology. Q2:08, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, 171 76 Stockholm, Sweden.
authors.forename: Ellie
authors.initials: E
authors.lastname: Landman
authors.affiliation: Division of Pediatric Endocrinology. Q2:08, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, 171 76 Stockholm, Sweden.|Department of Medical Sciences, Rm C1213, Örebro University and University Hospital, 701 85 Örebro, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Nilsson
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Barnes
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive, MSC-1103, Bethesda, Maryland 20892, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baron
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development / Q000235:genetics; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D006132:Growth Plate / Q000378:metabolism; D006984:Hypertrophy; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D013977:Tibia / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; D000071221:Enhancer of Zeste Homolog 2 Protein; C498408:Ezh1 protein, mouse; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2