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

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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
    Rm C1213, Örebro University 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)

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.

Suggested Citation

  • Julian C. Lui & Presley Garrison & Quang Nguyen & Michal Ad & Chithra Keembiyehetty & Weiping Chen & Youn Hee Jee & Ellie Landman & Ola Nilsson & Kevin M. Barnes & Jeffrey Baron, 2016. "EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13685
    DOI: 10.1038/ncomms13685
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