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EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy
Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Bethesda, Maryland, USA.
Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Bethesda, Maryland, USA.
Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Bethesda, Maryland, USA.
Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Bethesda, Maryland, USA.
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, 13685Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
London, United Kingdom: Nature Publishing Group, 2016. Vol. 7, 13685
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-53758DOI: 10.1038/ncomms13685ISI: 000388662100001PubMedID: 27897169ScopusID: 2-s2.0-84999143251OAI: oai:DiVA.org:oru-53758DiVA: diva2:1052063
Funder
Swedish Research Council, 521-2014-3063 2015-02227VINNOVA, 2014-01438Marianne and Marcus Wallenberg Foundation
Note

Funding Agencies:

Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH

Stockholm County Council

Byggmästare Olle Engkvist's Foundation

Stiftelsen Frimurare Barnhuset i Stockholm

Karolinska Institutet

Available from: 2016-12-05 Created: 2016-12-05 Last updated: 2017-01-03Bibliographically approved

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