7月6日,，四川大學(xué)華西口腔醫(yī)學(xué)院葉玲教授與美國加州大學(xué)洛杉磯分校牙學(xué)院王存玉教授合作研究了表觀遺傳調(diào)控在間充質(zhì)干細(xì)胞分化選擇中的作用機制,，撰寫的論文“Histone Demethylases KDM4B and KDM6B Promote Osteogenic Differentiation of Human MSCs”發(fā)表在Cell Stem Cell上，并成為該期封面文章! 該研究主要揭示了組蛋白去甲基化酶KDM4B和KDM6B調(diào)控間充質(zhì)干細(xì)胞成骨向分化的分子機制,。由于組蛋白去甲基化酶具有化學(xué)可修飾性，本研究成果為間充質(zhì)干細(xì)胞命運選擇的調(diào)控提供了全新的思路,，同時也為干細(xì)胞介導(dǎo)的再生醫(yī)學(xué)和代謝性骨疾病,，如骨質(zhì)疏松癥治療方法的研究開辟了新的方向。
人骨髓間充質(zhì)干/基質(zhì)細(xì)胞（MSCs）是一種多能性祖細(xì)胞,，具有多向分化潛能,，包括分化為成骨細(xì)胞和脂肪細(xì)胞。雖然對MSC命運轉(zhuǎn)錄調(diào)控的研究取得了重大進(jìn)展,，但對MSC分化表觀遺傳學(xué)調(diào)控人們確知之甚少,。
本研究表明，組蛋白去甲基化酶KDM4B和KDM6B通過消除H3K9me3和H3K27me3甲基化修飾,，在骨髓間充質(zhì)干細(xì)胞向成骨細(xì)胞分化的決定過程中發(fā)揮關(guān)鍵作用,。去除KDM4B或KDM6B顯著降低MSC向成骨細(xì)胞分化，并且增加向脂肪細(xì)胞的分化,。
其機制是,，KDM6B通過消除H3K27me3控制HOX基因的表達(dá)，而KDM4B消除H3K9me3以促進(jìn) DLX的表達(dá),。重要的是,，H3K27me3及H3K9me3陽性的骨髓MSCs在去除卵巢和衰老小鼠體內(nèi)顯著升高。在這些小鼠體內(nèi)脂肪生成作用是高度活躍的,。
由于組蛋白去甲基化酶是可化學(xué)修飾的,，KDM4B和KDM6B可能作為治療靶點，控制MSC分化命運的選擇,，并為骨代謝疾病,，如骨質(zhì)疏松癥的新治療方法的研發(fā)提供線索。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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Histone Demethylases KDM4B and KDM6B Promotes Osteogenic Differentiation of Human MSCs
Ling Ye, Zhipeng Fan, Bo Yu, Jia Chang, Khalid Al Hezaimi, Xuedong Zhou, No-Hee Park, Cun-Yu Wang
Human bone marrow mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells with multilineage differentiation potentials including osteogenesis and adipogenesis. While significant progress has been made in understanding transcriptional controls of MSC fate, little is known about how MSC differentiation is epigenetically regulated. Here we show that the histone demethylases KDM4B and KDM6B play critical roles in osteogenic commitment of MSCs by removing H3K9me3 and H3K27me3. Depletion of KDM4B or KDM6B significantly reduced osteogenic differentiation and increased adipogenic differentiation. Mechanistically, while KDM6B controlled HOX expression by removing H3K27me3, KDM4B promoted DLX expression by removing H3K9me3. Importantly, H3K27me3- and H3K9me3-positive MSCs of bone marrow were significantly elevated in ovariectomized and aging mice in which adipogenesis was highly active. Since histone demethylases are chemically modifiable, KDM4B and KDM6B may present as therapeutic targets for controlling MSC fate choices and lead to clues for new treatment in metabolic bone diseases such as osteoporosis.
