Plos Biology:骨质疏松症治疗新靶标

2018-11-27 佚名 中科院

近日,国际学术期刊 Plos Biology 在线发表了中国科学院生物化学与细胞生物学研究所邹卫国研究组的最新研究成果“H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells”,首次揭示了组蛋白甲基转移酶 SETD2 介导的组蛋白 H3k36 三甲基化修饰在骨髓间

近日,国际学术期刊 Plos Biology 在线发表了中国科学院生物化学与细胞生物学研究所邹卫国研究组的最新研究成果“H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells”,首次揭示了组蛋白甲基转移酶 SETD2 介导的组蛋白 H3k36 三甲基化修饰在骨髓间质干细胞(bone mesenchymal stem cells, BMSCs)命运决定中的作用,建立了骨骼系统衰老的小鼠模型,并揭示了骨质疏松症治疗新靶标。

在衰老过程中,骨髓间充质干细胞成骨能力下降,并伴有过多的脂肪生成,从而导致骨质疏松症。在过去的几十年中,BMSCs 谱系决定的转录水平调控得到诸多研究。衰老与表观遗传的改变密切相关。近年来,表观遗传对于 BMSCs 的影响受到关注。组蛋白甲基化状态被认为是 BMSC 向成骨系或脂肪系分化的重要调节因子。有报道称,抑制组蛋白修饰的 H3K27 三甲基化,H3K9 三甲基化等,对骨髓的脂肪发生有促进作用。然而,这些报道大多是在体外培养的细胞水平上完成,组蛋白修饰对 BMSCs 命运决定的体内影响知之甚少。

SETD2 (SET-domain-containing 2)是负责组蛋白 H3K36 三甲基化的甲基转移酶。在本项研究中,研究人员通过在 BMSCs 中条件性敲除 SETD2 基因,发现 5 周龄年轻小鼠骨髓腔中充满大量脂肪细胞,而骨量显着下降,模拟了老年性骨质疏松症的表型。

研究人员通过对野生型和模型小鼠 BMSCs 进行 RNA-seq 和 H3K36me3-ChIP-Seq 的联合分析,鉴定了 H3K36 三甲基化调控的关键因子脂多糖结合蛋白 LBP。LBP 是分泌型蛋白,在模型小鼠中表达下降。过表达 LBP 能够抑制 BMSCs 细胞向脂肪分化,促进成骨向分化。

进一步的机理研究表明,H3K36 的三甲基化水平可以调节LBP的转录起始和延伸。该工作揭示了组蛋白甲基转移酶 SETD2 介导的 H3k36 三甲基化在骨髓间质干细胞命运决定中的作用,同时为骨质疏松的治疗提供了潜在的药物靶点。

这项工作由通讯作者邹卫国研究员指导,在读博士生王丽君,上海交通大学附属仁济医院副研究员牛宁宁,副研究员李力为本文的共同第一作者。该研究得到了生化与细胞所周波研究员的大力帮助。该研究得到了中科院先导专项、国家自然科学基金杰青项目、面上项目的经费资助,同时获得了生化与细胞所公共技术服务中心动物实验技术平台、细胞生物学技术平台和分子生物学技术平台的技术支持。

原始出处:

Wang L,Niu N,Li L,et al.H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells.PLoS Biol,2018,16(11):e2006522.

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    2019-03-27 sunylz
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    2018-11-29 zhaojie88
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    2018-11-29 Eleven17

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