项目名称: miR-455双向调控MSCs成软骨分化和退变中表观遗传学去阻遏的机制研究
项目编号: No.81472101
项目类型: 面上项目
立项/批准年度: 2015
项目学科: 医药、卫生
项目作者: 廖威明
作者单位: 中山大学
项目金额: 90万元
中文摘要: 组蛋白乙酰化、DNA甲基化修饰和miRNAs等表观遗传学机制在间质干细胞成软骨分化和软骨退变过程中发挥重要作用。课题组前期发现miR-455具备罕见的促成软骨/退变双向调控能力,无法用以往报道的miRNAs调控成软骨/退变的模型加以解释。我们认为miR-455可能通过调控下游表观遗传学机制,包括组蛋白乙酰化、DNA甲基化,发挥去阻遏作用,从而同时促进间质干细胞成软骨分化和软骨退变。预实验结果发现miR-455可能靶向抑制HDAC2、3或Dnmt3a表达,解除其组蛋白去乙酰化、DNA甲基化产生的广泛基因抑制,发挥阻遏间质干细胞成软骨分化的作用。本研究我们拟采用新技术miRTRAP鉴定miR-455的全部靶基因,从中找出表观遗传学调控相关的靶基因,从细胞-组织-整体层次证明我们的理论猜测。该项目将首次一次性获得特定miRNA的全部靶基因并提出miRNAs调控干细胞分化的新模型。
中文关键词: miR-455;表观遗传学;成软骨分化;软骨退变;间充质干细胞
英文摘要: The epigenetic regulations, including histone acetylation, DNA Methylation, and miRNAs, have been proved to exert important effects on chondrogenesis of mesenchymal stem cells and degradation of cartilage. Our previous work identified that miR-455 has a rare dual-way effect to prompt chondrogenesis and cartilage degradation simultaneously, which can barely be explained with models of previous reports regarding miRNAs-chondrogenesis-degradation. We thus proposed a novel theoretical conjecture: miR-455 exerts a derepressive effect to prompts chondrogenesis and cartilage degradation simultaneously via the downstream regulation of epigenetic mechanisms, including histone acetylation, DNA Methylation, etc.. Our preliminary results indicated that with specifical inhibition of the HDAC2, 3, or Dnmt3a expression, miR-455 might relieve the acetylation of histone and methylation of DNA, the following repression of transcription, and prompt chondrogenesis of mesenchymal stem cells. We planned to identify the whole target gene profile of miR-455 with new technique of miRTRAP, find the target genes related to epigenetic mechanisms from the whole profile, and verify the theoretical conjecture in cell-tissue-body levels. This project is the first to identify the whole target gene profile of a specific miRNA and the first to propose a novel model of miRNA regulation of stem cell differentiation.
英文关键词: miR-455;epigenetic;chondrogenesis;degeneration;mesenchymal stem cell