<i>EZH2</i> and <i>KDM6A</i> Act as an Epigenetic Switch to Regulate Mesenchymal Stem Cell Lineage Specification

Hemming, Sarah; Cakouros, Dimitrios; Isenmann, Sandra; Cooper, Lachlan; Menicanin, Danijela; Zannettino, Andrew C.W.; Gronthos, Stan

doi:10.1002/stem.1573

Cited by 233 publications

(261 citation statements)

References 49 publications

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“…Thus, overexpression of EZH2 protein in human MSCs impairs their potential to differentiate to osteoblasts, in part by producing increased levels of H3K27me3 at regulatory regions of bone-related target genes, including Runx2 and osteocalcin/ Bglap (34). In agreement with this report, CDK1-dependent phosphorylation of EZH2 at residue Thr-487, which prevents formation of an active PRC2 complex, promotes differentiation of human MSCs to osteoblasts (35).…”

supporting

confidence: 86%

Epigenetic Control of the Bone-master Runx2 Gene during Osteoblast-lineage Commitment by the Histone Demethylase JARID1B/KDM5B

Rojas

Aguilar

Henríquez

et al. 2015

Journal of Biological Chemistry

121

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Background: Runx2 is the master regulator of osteoblast differentiation. Results: JARID1B/KDM5B is a key component of the epigenetic mechanisms that control Runx2 expression during osteoblast and myoblast differentiation. These mechanisms operate at the P1 promoter. Conclusion: Epigenetic mechanisms regulate Runx2 expression and osteoblast-lineage commitment. Significance: The work provides new mechanistic insights of Runx2 gene expression control during mesenchymal fate determination.

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supporting

confidence: 86%

Epigenetic Control of the Bone-master Runx2 Gene during Osteoblast-lineage Commitment by the Histone Demethylase JARID1B/KDM5B

Rojas

Aguilar

Henríquez

et al. 2015

Journal of Biological Chemistry

121

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“…More recently, enforced expression of EZH2 in human bone marrow-derived MSC promoted adipogenesis in vitro and inhibited osteogenic differentiation potential in vitro and in vivo [25]. Conversely, inhibition of EZH2 enzymatic activity and knockdown of EZH2 gene expression inhibited adipogenesis and promoted osteogenic differentiation by MSC [25].…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, inhibition of EZH2 enzymatic activity and knockdown of EZH2 gene expression inhibited adipogenesis and promoted osteogenic differentiation by MSC [25]. EZH2 has been reported to be regulated through phosphorylation at Thr 487 by cyclin-dependent kinase 1 (CDK1).…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Hemming

Cakouros

Vandyke

et al. 2016

Stem Cells and Development

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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.

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“…In addition to the transcription factors and signaling molecules, the Jumonji-domain-containing histone demethylases have been shown to be of great importance in the control of osteogenic differentiation (20,21). Nucleolar protein 66 (NO66) is a Jumonji C-domain-containing protein and is conserved in eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

“…Bone formation and growth are also controlled by a broad signaling network including IGF, bone morphogenetic protein (BMP), and members of the Wnt family (11)(12)(13)(14)(15). Previous studies showed that dysregulation of these signaling molecules results in abnormal bone growth (16)(17)(18)(19).In addition to the transcription factors and signaling molecules, the Jumonji-domain-containing histone demethylases have been shown to be of great importance in the control of osteogenic differentiation (20,21). Nucleolar protein 66 (NO66) is a Jumonji C-domain-containing protein and is conserved in eukaryotes.…”

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confidence: 99%

Mesenchyme‐specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation

et al. 2015

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Previous studies showed that nucleolar protein 66 (NO66), the Jumonji C-domain-containing histone demethylase for methylated histone H3K4 and H3K36 (H3K36me), negatively regulates osteoblast differentiation in vitro by inhibiting the activity of transcription factor osterix (Osx). However, whether NO66 affects mammalian skeletogenesis in vivo is not yet known. Here, we generated transgenic (TG) mice overexpressing a flag-tagged NO66 transgene driven by the Prx1 (paired related homeobox 1) promoter. We found that NO66 overexpression in Prx1-expressing mesenchymal cells inhibited skeletal growth and bone formation. The inhibitory phenotype was associated with >50% decreases in chondrocyte/osteoblast proliferation and differentiation. Moreover, we found that in bones of NO66-TG mice, expression of Igf1, Igf1 receptor (Igf1r), runt-related transcription factor 2, and Osx was significantly down-regulated (P < 0.05). Consistent with these results, we observed >50% reduction in levels of phosphorylated protein kinase B (Akt) and H3K36me3 in bones of NO66-TG mice, suggesting an inverse correlation between NO66 histone demethylase and the activity of IGF1R/Akt signaling. This correlation was further confirmed by in vitro assays of C2C12 cells with NO66 overexpression. We propose that the decrease in the IGF1R/Akt signaling pathway in mice with mesenchymal overexpression of NO66 may contribute in part to the inhibition of skeletal growth and bone formation.-Chen, Q., Zhang, L., de Crombrugghe, B., Krahe, R. Mesenchyme-specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation. FASEB J. 29, 2555-2565 (2015). www.fasebj.org Key Words: histone demethylase • transgenic mice • IGF1R/Akt signaling pathway • osterix THE MAJORITY OF THE MAMMALIAN skeleton is composed of 2 types of tissues: cartilage and bone. Cartilage is made by chondrocytes that are required for the longitudinal growth of bones. Bone forms through 2 distinct processes: intramembranous and endochondral ossification. In intramembranous ossification, bones form directly from the differentiation of mesenchymal progenitor cells, which then differentiate into cells of osteoblast lineage including preosteoblasts, osteoblasts, and osteocytes. However, in endochondral ossification, osteochondroprogenitors, which derive from mesenchymal progenitors, segregate into either chondrocytes that form a cartilage template or osteoblast precursors, which differentiate to form bone tissue that replaces the cartilage template. The progression through mesenchymal condensation, chondrocyte differentiation, and osteogenic-lineage commitment involves 3 key transcription factors: SRY-related HMG-box 9 (Sox9), runt-related transcription factor 2 (Runx2), and osterix (Osx). During endochondral ossification, Sox9 is required for mesenchymal progenitor condensation and expression of type II collagen (Col2) a1 (1-3). Runx2 has a dual role in the regulation of osteogenic-lineage commitment and the differentiation of mature chondrocytes (4-8). R...

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

Cited by 233 publications

References 49 publications

Epigenetic Control of the Bone-master Runx2 Gene during Osteoblast-lineage Commitment by the Histone Demethylase JARID1B/KDM5B

Epigenetic Control of the Bone-master Runx2 Gene during Osteoblast-lineage Commitment by the Histone Demethylase JARID1B/KDM5B

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Mesenchyme‐specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation

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