EZH2 and KDM6A Act as an Epigenetic Switch to Regulate Mesenchymal Stem Cell Lineage Specification

Author:

Hemming Sarah1,Cakouros Dimitrios1,Isenmann Sandra1,Cooper Lachlan1,Menicanin Danijela1,Zannettino Andrew23,Gronthos Stan13

Affiliation:

1. Mesenchymal Stem Cell Laboratory School of Medical Sciences, Faculty of Health Sciences, South Australia, Australia

2. Myeloma Research Laboratory School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, South Australia, Australia

3. Centre for Stem Cell Research Robinson Institute, University of Adelaide, South Australia, Australia

Abstract

Abstract The methyltransferase, Enhancer of Zeste homology 2 (EZH2), trimethylates histone 3 lysine 27 (H3K27me3) on chromatin and this repressive mark is removed by lysine demethylase 6A (KDM6A). Loss of these epigenetic modifiers results in developmental defects. We demonstrate that Ezh2 and Kdm6a transcript levels change during differentiation of multipotential human bone marrow-derived mesenchymal stem cells (MSC). Enforced expression of Ezh2 in MSC promoted adipogenic in vitro and inhibited osteogenic differentiation potential in vitro and in vivo, whereas Kdm6a inhibited adipogenesis in vitro and promoted osteogenic differentiation in vitro and in vivo. Inhibition of EZH2 activity and knockdown of Ezh2 gene expression in human MSC resulted in decreased adipogenesis and increased osteogenesis. Conversely, knockdown of Kdm6a gene expression in MSC leads to increased adipogenesis and decreased osteogenesis. Both Ezh2 and Kdm6a were shown to affect expression of master regulatory genes involved in adipogenesis and osteogenesis and H3K27me3 on the promoters of master regulatory genes. These findings demonstrate an important epigenetic switch centered on H3K27me3 which dictates MSC lineage determination. Stem Cells  2014;32:802–815

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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