Epigenetic control of skeletal development by the histone methyltransferase Ezh2

Amel Dudakovic, Emily T. Camilleri, Fuhua Xu, Scott M. Riester, Meghan E. McGee-Lawrence, Elizabeth Bradley, Christopher R. Paradise, Eric A. Lewallen, Roman Thaler, David R Deyle, A. Noelle Larson, David G. Lewallen, Allan B Dietz, Gary S. Stein, Martin A. Montecino, Jennifer J Westendorf, Andre J van Wijnen

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Abstract

Epigenetic control of gene expression is critical for normal fetal development. However, chromatin-related mechanisms that activate bone-specific programs during osteogenesis have remained underexplored. Therefore, we investigated the expression profiles of a large cohort of epigenetic regulators (>300) during osteogenic differentiation of human mesenchymal cells derived from the stromal vascular fraction of adipose tissue (AMSCs). Molecular analyses establish that the polycomb group protein EZH2 (enhancer of zeste homolog 2) is down-regulated during osteoblastic differentiation of AMSCs. Chemical inhibitor and siRNA knockdown studies show that EZH2, a histone methyltransferase that catalyzes trimethylation of histone 3 lysine 27 (H3K27me3), suppresses osteogenic differentiation. Blocking EZH2 activity promotes osteoblast differentiation and suppresses adipogenic differentiation of AMSCs. High throughput RNA sequence (mRNASeq) analysis reveals that EZH2 inhibition stimulates cell cycle inhibitory proteins and enhances the production of extracellular matrix proteins. Conditional genetic loss of Ezh2 in uncommitted mesenchymal cells (Prrx1-Cre) resultsinmultiple defectsinskeletal patterning and bone formation, including shortened forelimbs, craniosynostosis, and clinodactyly. Histological analysis and mRNASeq profiling suggest that these effects are attributable to growth plate abnormalities and premature cranial suture closure because of precocious maturation of osteoblasts. We conclude that the epigenetic activity of EZH2 is required for skeletal patterning and development, but EZH2 expression declines during terminal osteoblast differentiation and matrix production.

Original languageEnglish (US)
Pages (from-to)27604-27617
Number of pages14
JournalJournal of Biological Chemistry
Volume290
Issue number46
DOIs
StatePublished - Nov 13 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Dudakovic, A., Camilleri, E. T., Xu, F., Riester, S. M., McGee-Lawrence, M. E., Bradley, E., Paradise, C. R., Lewallen, E. A., Thaler, R., Deyle, D. R., Larson, A. N., Lewallen, D. G., Dietz, A. B., Stein, G. S., Montecino, M. A., Westendorf, J. J., & van Wijnen, A. J. (2015). Epigenetic control of skeletal development by the histone methyltransferase Ezh2. Journal of Biological Chemistry, 290(46), 27604-27617. https://doi.org/10.1074/jbc.M115.672345