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

Julian C. Lui (), Presley Garrison, Quang Nguyen, Michal Ad, Chithra Keembiyehetty, Weiping Chen, Youn Hee Jee, Ellie Landman, Ola Nilsson, Kevin M. Barnes and Jeffrey Baron
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Julian C. Lui: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Presley Garrison: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Quang Nguyen: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Michal Ad: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Chithra Keembiyehetty: Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Weiping Chen: Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Youn Hee Jee: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Ellie Landman: Karolinska Institutet and University Hospital
Ola Nilsson: Karolinska Institutet and University Hospital
Kevin M. Barnes: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Jeffrey Baron: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13685

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