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

Julian C Lui,Weiping Chen,Ellie Landman,Quang Nguyen,Youn Hee Jee,Chithra Keembiyehetty,Ola Nilsson,Jeffrey Baron,Michal Ad,Presley Garrison,Kevin M Barnes

doi:10.1038/ncomms13685

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.

Highlights

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
SUZ12, EED, RbAp48 and EZH1/EZH2, the polycomb repressor complex 2 (PRC2) is responsible for catalysing the trimethylation of histone H3 at lysine 27 (H3K27me3)[5], which serves as an epigenetic signal for chromatin condensation and transcriptional repression
We speculate that this greater effect on skeletal growth after birth in some way reflects the major differences in the structure and function of the prenatal and postnatal growth plate cartilage[13]

Summary

Introduction

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. We show that the combined loss of Ezh[1] and Ezh[2] in chondrocytes severely impairs skeletal growth in mice Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. Chondrocytes in the RZ serve as stem-cell-like precursors, which are capable of self-renewal and give rise to clones of proliferative chondrocytes in the adjacent PZ These clones are arranged in columns parallel to the long axis of the bone and undergo rapid proliferation. Mutations in the DNA methyltransferase DNMT3A gene were reported to cause a distinct overgrowth syndrome with intellectual disability[4] Another important chromatin modifier, the polycomb repressor complex 2 (PRC2), regulates longitudinal bone growth. In the PZ, PRC2 suppresses the expression of Cdkn2a/b to allow normal cell cycle progression, while in the HZ, PRC2 suppresses Igfbp3/5 expression, thereby promoting IGF signalling and chondrocyte hypertrophy

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Results

Conclusion