EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy

被引：80

作者：

Lui, Julian C. ^{[1
]}

Garrison, Presley ^{[1
]}

Nguyen, Quang ^{[1
]}

Ad, Michal ^{[1
]}

Keembiyehetty, Chithra ^{[2
]}

Chen, Weiping ^{[2
]}

Jee, Youn Hee ^{[1
]}

Landman, Ellie ^{[3
,4
]}

Nilsson, Ola ^{[3
,4
,5
,6
]}

Barnes, Kevin M. ^{[1
]}

Baron, Jeffrey ^{[1
]}

机构：

[1] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Dev, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA

[2] NIDDK, Genom Core, NIH, Bldg8,Room 1A11,8 Ctr Dr, Bethesda, MD 20892 USA

[3] Karolinska Inst, Div Pediat Endocrinol Q2 08, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden

[4] Univ Hosp, S-17176 Stockholm, Sweden

[5] Univ Orebro, Dept Med Sci, Rm C1213, S-70185 Orebro, Sweden

[6] Univ Hosp, S-70185 Orebro, Sweden

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

瑞典研究理事会;

关键词：

GENE-EXPRESSION; WEAVER SYNDROME; LYSINE; 27; MUTATIONS; METHYLATION; H3K27; P16(INK4A); PATTERNS; PLATE;

D O I：

10.1038/ncomms13685

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

共 42 条

[1] The methyltransferases enhancer of zeste homolog (EZH) 1 and EZH2 control hepatocyte homeostasis and regeneration [J].