Histone Demethylases KDM4B and KDM6B Promotes Osteogenic Differentiation of Human MSCs

Ye, Ling; Fan, Zhipeng; B, Yu; Chang, Jichuan; Hezaimi, Khalid Al; Zhou, Xuedong; Park, No-Hee; Wang, Cun‐Yu

doi:10.1016/j.stem.2012.04.009

Cited by 278 publications

(303 citation statements)

References 60 publications

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“…Furthermore, EZH2 does not only act on these genes identified in this study but regulation of RUNX2 and WNT genes is also critical for the lineage specification [24][25][26]. Recent studies from our laboratory, and others, have identified the role of the histone H3 lysine 27 demethylase KDM6A and KDM6B in regulating MSC osteogenic differentiation [25,62]. We predict that these demethylases together or individually may be responsible for the removal of H3K27me3 from the TSS of ZBTB16, MX1, and FHL-1 during MSC to osteogenic lineage commitment.…”

Section: Discussionmentioning

confidence: 53%

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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Section: Discussionmentioning

confidence: 53%

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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“…Thus, the histone demethylases JMJD2B (KDM4B) and JMJD3 (KDM6B) appear to be important components in the processes that regulate osteoblast lineage commitment of human MSCs (36). Nevertheless, the presence of osteoblast master regulators among the group of specific direct targets of these enzymes was not confirmed, indicating that the enzymes may be operating through an indirect mechanism or, alternatively, that unidentified demethylases are directly involved.…”

mentioning

confidence: 99%

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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“…Conversely, the depletion of KDM4B significantly decreased the protein levels of elastin and LOX in the BMSCs, suggesting that KDM4B was required for the BMSC differentiation into ligament fibroblasts. Ye et al reported that the depletion of KDM4B significantly reduced the osteogenic differentiation of MSCs in vitro and in vivo [37]. Lee et al also reported that KDM4B overexpression significantly enhanced the chondrogenic differentiation and that KDM4B depletion using shRNA significantly reduced the chondrogenic potential [38].…”

Section: Discussionmentioning

confidence: 99%

Mechanical stretching promotes the differentiation of BMSC into pelvic floor ligament fibroblasts

Zhao¹,

Wang²,

Ren³

et al. 2018

Oncotarget

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Pelvic floor dysfunction (PFD) is a prevalent and debilitating condition in agingwomen that is associated with weakened pelvic connective tissue. Fibroblasts are the main component of pelvic connective tissue and play a vital role in the maintenance of the pelvic organ. Mechanical stretching is a known modulator leading to the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). In this paper, we measured the lysyl oxidase (LOX), elastin and KDM4B expression in cultured BMSCs under different cyclic mechanical stretch (CMS) conditions via Western blot assays. Our findings indicated that the expression of these proteins was significantly higher in the CMS group than in the normal control group, and 10% CMS at a 0.5 Hz frequency had the best stimulatory effect. We further evaluated the influence of KDM4B on LOX and elastin expression via knockdown and overexpression of KDM4B in BMSCs. Chromatin immunoprecipitation (ChIP)-PCR analysis was performed to determine how H3K9me3 and KDM4B affect the regulatory regions of LOX and elastin in BMSCs subjected to 10% CMS combined with KDM4B knockdown. Finally, we verified the expression of KDM4B under CMS in vivo by subcutaneously transplanting KDM4B-overexpressing BMSCs into mice via immunofluorescence assays. The results showed that activating KDM4B by mechanical stretching increased the protein and gene expression levels of LOX and elastin and induced more LOX-positive cells in the BMSCs. These data suggest that CMS contributes to the differentiation of mesenchymal stem cells (MSCs) into fibroblasts, which indicates its potential use as a cell-based therapy for PFD.

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Histone Demethylases KDM4B and KDM6B Promotes Osteogenic Differentiation of Human MSCs

Cited by 278 publications

References 60 publications

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

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

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

Mechanical stretching promotes the differentiation of BMSC into pelvic floor ligament fibroblasts

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