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Type: Journal article
Title: Identification of novel EZH2 targets regulating osteogenic differentiation in mesenchymal stem cells
Author: Hemming, S.
Cakouros, D.
Vandyke, K.
Davis, M.
Zannettino, A.
Gronthos, S.
Citation: Stem Cells and Development, 2016; 25(12):909-921
Publisher: Mary Ann Liebert, Inc.
Issue Date: 2016
ISSN: 1547-3287
Statement of
Sarah Hemming, Dimitrios Cakouros, Kate Vandyke, Melissa J. Davis, Andrew C.W. Zannettino and Stan Gronthos
Abstract: Histone three lysine 27 (H3K27) methyltransferase enhancer of zeste homolog 2 (EZH2) is a critical epigenetic modifier, which regulates gene transcription through the trimethylation of the H3K27 residue leading to chromatin compaction and gene repression. EZH2 has previously been identified to regulate human bone marrow-derived mesenchymal stem cells (MSC) lineage specification. MSC lineage specification is regulated by the presence of EZH2 and its H3K27me3 modification or the removal of the H3K27 modification by lysine demethylases 6A and 6B (KDM6A and KDM6B). This study used a bioinformatics approach to identify novel genes regulated by EZH2 during MSC osteogenic differentiation. In this study, we identified the EZH2 targets, ZBTB16, MX1, and FHL1, which were expressed at low levels in MSC. EZH2 and H3K27me3 were found to be present along the transcription start site of their respective promoters. During osteogenesis, these genes become actively expressed coinciding with the disappearance of EZH2 and H3K27me3 on the transcription start site of these genes and the enrichment of the active H3K4me3 modification. Overexpression of EZH2 downregulated the transcript levels of ZBTB16, MX1, and FHL1 during osteogenesis. Small interfering RNA targeting of MX1 and FHL1 was associated with a downregulation of the key osteogenic transcription factor, RUNX2, and its downstream targets osteopontin and osteocalcin. These findings highlight that EZH2 not only acts through the direct regulation of signaling modules and lineage-specific transcription factors but also targets many novel genes important for mediating MSC osteogenic differentiation.
Keywords: Osteogenesis; Enhancer of Zeste Homolog 2 Protein
Rights: Copyright 2016, Mary Ann Liebert, Inc.
RMID: 0030047378
DOI: 10.1089/scd.2015.0384
Appears in Collections:Medicine publications

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