表观遗传学

7月6日，四川大学华西口腔医学院叶玲教授与美国加州大学洛杉矶分校牙学院王存玉教授合作研究了表观遗传调控在间充质干细胞分化选择中的作用机制，撰写的论文“Histone Demethylases KDM4B and KDM6B Promote Osteogenic Differentiation of Human MSCs”发表在Cell Stem Cell上，并成为该期封面文章! 该研究主要揭示了组蛋白去甲基化酶KDM4B和KDM6B调控间充质干细胞成骨向分化的分子机制。由于组蛋白去甲基化酶具有化学可修饰性，本研究成果为间充质干细胞命运选择的调控提供了全新的思路，同时也为干细胞介导的再生医学和代谢性骨疾病，如骨质疏松症治疗方法的研究开辟了新的方向。

人骨髓间充质干/基质细胞（MSCs）是一种多能性祖细胞，具有多向分化潜能，包括分化为成骨细胞和脂肪细胞。虽然对MSC命运转录调控的研究取得了重大进展，但对MSC分化表观遗传学调控人们确知之甚少。

本研究表明，组蛋白去甲基化酶KDM4B和KDM6B通过消除H3K9me3和H3K27me3甲基化修饰，在骨髓间充质干细胞向成骨细胞分化的决定过程中发挥关键作用。去除KDM4B或KDM6B显著降低MSC向成骨细胞分化，并且增加向脂肪细胞的分化。

其机制是，KDM6B通过消除H3K27me3控制HOX基因的表达，而KDM4B消除H3K9me3以促进 DLX的表达。重要的是，H3K27me3及H3K9me3阳性的骨髓MSCs在去除卵巢和衰老小鼠体内显著升高。在这些小鼠体内脂肪生成作用是高度活跃的。

由于组蛋白去甲基化酶是可化学修饰的，KDM4B和KDM6B可能作为治疗靶点，控制MSC分化命运的选择，并为骨代谢疾病，如骨质疏松症的新治疗方法的研发提供线索。


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.