Regulation of Stem Cell Differentiation by Histone Methyltransferases and Demethylases

Pasini, Diego; Bracken, Adrian P.; Agger, Karl; Christensen, Jesper; Hansen, Klaus; Cloos, Paul A.; Helin, Kristian

doi:10.1101/sqb.2008.73.009

Cited by 42 publications

(24 citation statements)

References 98 publications

(147 reference statements)

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“…We showed that the expression of ChM-I was down-regulated by histone modifications in stem cells and some types of differentiated cells. The epigenetic status is induced and maintained by a number of intrinsic histone modifiers (30). In this study, we found that YY1 and p300 are main modifiers of histone associated with the core-promoter region of the ChM-I gene.…”

Section: Discussionmentioning

confidence: 65%

Histone Modifiers, YY1 and p300, Regulate the Expression of Cartilage-specific Gene, Chondromodulin-I, in Mesenchymal Stem Cells

Aoyama

Okamoto

Fukiage

et al. 2010

Journal of Biological Chemistry

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Elucidating the regulatory mechanism for tissue-specific gene expression is key to understanding the differentiation process. The chondromodulin-I gene (ChM-I) is a cartilage-specific gene, the expression of which is regulated by the transcription factor, Sp3. The binding of Sp3 to the core-promoter region is regulated by the methylation status of the Sp3-binding motif as we reported previously. In this study, we have investigated the molecular mechanisms of the down-regulation of ChM-I expression in mesenchymal stem cells (MSCs) and normal mesenchymal tissues other than cartilage. The core-promoter region of cells in bone and peripheral nerve tissues was hypermethylated, whereas the methylation status in cells of other tissues including MSCs did not differ from that in cells of cartilage, suggesting the presence of inhibitory mechanisms other than DNA methylation. We found that a transcriptional repressor, YY1, negatively regulated the expression of ChM-I by recruiting histone deacetylase and thus inducing the deacetylation of associated histones. As for a positive regulator, we found that a transcriptional co-activator, p300, bound to the core-promoter region with Sp3, inducing the acetylation of histone. Inhibition of YY1 in combination with forced expression of p300 and Sp3 restored the expression of ChM-I in cells with a hypomethylated promoter region, but not in cells with hypermethylation. These results suggested that the expression of tissue-specific genes is regulated in two steps; reversible down-regulation by transcriptional repressor complex and tight down-regulation via DNA methylation.

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Section: Discussionmentioning

confidence: 65%

Histone Modifiers, YY1 and p300, Regulate the Expression of Cartilage-specific Gene, Chondromodulin-I, in Mesenchymal Stem Cells

Aoyama

Okamoto

Fukiage

et al. 2010

Journal of Biological Chemistry

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“…Epigenetic modifications of the chromatin structures, including histone deacetylations, play an essential role in regulating the pluripotency of stem cells and progenitor reprogramming [24,25,26,27,45,46,47]. Hdacs link chromatin structure and transcription factors, and exert epigenetic control of transcriptional activity by removing negatively charged acetyl groups from lysine residues in histones, leading to chromatin condensation and limiting the accessibility of transcription factors to the DNA.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Histone Deacetylases Potentiates BMP9-Induced Osteogenic Signaling in Mouse Mesenchymal Stem Cells

Wang

Liu

et al. 2013

Cell Physiol Biochem

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Background/Aims: We have demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent BMPs in regulating osteoblast differentiation of mesenchymal stem cells (MSCs) although the molecular mechanism underlying BMP9-induced osteogenesis remains to be fully elucidated. It is known that epigenetic regulations play an important role in regulating the stem cell potency and lineage commitment. Here, we investigate if the inhibition of histone deacetylases (Hdacs) affects BMP9-induced osteogenic differentiation of MSCs. Methods: Using the Hdac inhibitor trichostatin A (TSA), we assess that TSA enhances BMP9-mediated osteogenic markers and matrix mineralization in MSCs, and bone formation in mouse embryonic limb explants. Results: We find that the endogenous expression of most of the 11 Hdacs is readily detectable in MSCs. BMP9 is shown to induce most Hdacs in MSCs. We demonstrate that TSA potentiates BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs, as well as late osteogenic markers osteopontin (OPN) and osteocalcin (OCN) and matrix mineralization. Fetal limb explant culture studies reveal that TSA potentiates BMP9-induced endochondral bone formation, possibly by expanding hypertrophic chondrocyte zone of growth plate. Conclusion: Our findings strongly suggest histone deacetylases may play an important role in fine-tuning BMP9-mediated osteogenic signaling through a negative feedback network in MSCs. Thus, Hdac inhibitors may be used as novel therapeutics for bone fracture healing.

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“…The three polycomb group proteins of the PRC2 complex are all required for EZH2 histone methyltransferase activity, and loss of either Suz12 or Eed results in a global loss of H3K27me2 and -me3 (29,30). Importantly, the activity of the PRC2 complex is required for development, stem cell differentiation, and epigenetic inheritance (8,(31)(32)(33)(34). For example, loss of Suz12 causes embryonic death during early postimplantation stages, and the Suz12-deficient embryos contain diminished levels of H3K27me2 and H3K27me3 in vivo (34).…”

mentioning

confidence: 99%

Quantitative Mass Spectrometry of Histones H3.2 and H3.3 in Suz12-deficient Mouse Embryonic Stem Cells Reveals Distinct, Dynamic Post-translational Modifications at Lys-27 and Lys-36

Jung

Pasini

Helin

et al. 2010

Molecular & Cellular Proteomics

126

109

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Regulation of Stem Cell Differentiation by Histone Methyltransferases and Demethylases

Cited by 42 publications

References 98 publications

Histone Modifiers, YY1 and p300, Regulate the Expression of Cartilage-specific Gene, Chondromodulin-I, in Mesenchymal Stem Cells

Histone Modifiers, YY1 and p300, Regulate the Expression of Cartilage-specific Gene, Chondromodulin-I, in Mesenchymal Stem Cells

Inhibition of Histone Deacetylases Potentiates BMP9-Induced Osteogenic Signaling in Mouse Mesenchymal Stem Cells

Quantitative Mass Spectrometry of Histones H3.2 and H3.3 in Suz12-deficient Mouse Embryonic Stem Cells Reveals Distinct, Dynamic Post-translational Modifications at Lys-27 and Lys-36

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