Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

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 (&...

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Bibliographic Details
Published in:	The Journal of biological chemistry 2015-11, Vol.290 (46), p.27604-27617
Main Authors:	Dudakovic, Amel, Camilleri, Emily T., Xu, Fuhua, Riester, Scott M., McGee-Lawrence, Meghan E., Bradley, Elizabeth W., Paradise, Christopher R., Lewallen, Eric A., Thaler, Roman, Deyle, David R., Larson, A. Noelle, Lewallen, David G., Dietz, Allan B., Stein, Gary S., Montecino, Martin A., Westendorf, Jennifer J., van Wijnen, Andre J.
Format:	Article
Language:	eng
Subjects:	adipogenesis Adipose Tissue - cytology Animals Body Patterning - genetics bone Bone and Bones - embryology Cell Differentiation - genetics Cell Line Enhancer of Zeste Homolog 2 Protein Epigenesis, Genetic epigenetics Ezh2 Gene Regulation Growth Plate - abnormalities histone methylation Histone Methyltransferases Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Histones - metabolism Humans mesenchymal stem cells (MSCs) Mesenchymal Stem Cells - cytology Mice osteoblast Osteoblasts - cytology osteogenesis Osteogenesis - genetics Polycomb Repressive Complex 2 - antagonists & inhibitors Polycomb Repressive Complex 2 - genetics Polycomb Repressive Complex 2 - metabolism RNA, Small Interfering - genetics
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Summary:	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) results in multiple defects in skeletal 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. Osteogenic differentiation is initiated by transcriptional and post-transcriptional epigenetic mechanisms. Inhibition of H3K27 methyltransferase EZH2 enhances osteogenic commitment of human mesenchymal progenitors, and its depletion in mouse mesenchymal cells causes multiple skeletal abnormalities. EZH2 is required for skeletal patterning and bone formation. EZH2-dependent epigenetic mechanisms control osteogenesis both in vitro and in vivo.
ISSN:	0021-9258 1083-351X