H3K9乙酰化在间充质干细胞成骨向分化过程中开关作用的机制研究

项目名称： H3K9乙酰化在间充质干细胞成骨向分化过程中开关作用的机制研究

项目编号： No.81500822

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张萍

作者单位： 北京大学

项目金额： 18万元

中文摘要： 间充质干细胞(MSCs)是骨组织工程种子细胞的重要来源之一。如何有效促进MSCs的成骨向分化仍是亟待解决的问题。在转录水平，对MSCs分化潜能的机制研究已取得了较大的进展，但表观遗传在MSCs成骨定向分化中的调控机制还知之甚少。本课题组前期研究首次发现人骨髓或脂肪MSCs成骨分化过程中，组蛋白H3K9乙酰化水平显著上升；且负责H3K9乙酰化修饰的乙酰化酶PCAF和去乙酰化酶SIRT6均在MSCs的成骨分化过程中发挥重要作用。本项目拟以人骨髓和脂肪MSCs为研究对象，以骨质疏松动物模型为验证，率先探讨H3K9乙酰化调控MSCs成骨向分化的作用机制，明确新的成骨相关靶基因，阐明H3K9乙酰化酶PCAF和去乙酰化酶SIRT6协同调控MSCs成骨分化过程的先后次序和因果关系；对未来以组蛋白H3K9乙酰化为切入点，发现小分子药物并实现表观调控，为骨再生研究的临床转化打下坚实基础。

中文关键词： 间充质干细胞；成骨分化；H3K9乙酰化；SIRT6；PCAF

英文摘要： Human bone marrow or adipose-derived 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 showed that the H3K9 acetylation was greatly increased during the osteogenic differentiation of MSCs. Meanwhile, H3K9 acetylase/deacetylase PCAF and SIRT6 were both involved in the process of osteogenic commitment. We planed to investigate the mechanism of H3K9 acetylation regulating the osteogenic commitment by using MSCs and osteoporosis mice moldel. Since histone acetylases/deacetylases are chemically modifiable, SIRT6 and PCAF may present as therapeutic targets for controlling MSC fate choices and lead to clues for new treatment in metabolic bone diseases such as osteoporosis.

英文关键词： mesenchymal stem cells;osteogenic differentiation;H3K9 acetylation;SIRT6;p300/CBP-associated factor