Lhx2调控上皮-间质转换的表观遗传学机制研究及其在神经外胚层细胞编程与重编程中的作用

项目名称： Lhx2调控上皮-间质转换的表观遗传学机制研究及其在神经外胚层细胞编程与重编程中的作用

项目编号： No.91519323

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 章小清

作者单位： 同济大学

项目金额： 75万元

中文摘要： 在多能干细胞向三胚层编程分化以及成体细胞向诱导多能干细胞重编程的过程中均伴随有明显的上皮细胞（“E”）和间质细胞（“M”）类型间的相互转换。这种“E”-“M”转换或“M”-“E”转换是否是实现编程和重编程过程所必需，其转换的关键决定因素与分子机制如何尚有待明确。我们的前期研究发现，转录因子Lhx2能诱导人胚胎干细胞发生“E”-“M”转换，而且这种转换是人胚胎干细胞发育为神经外胚层细胞的先决条件。在本申请中，我们将首先确立Lhx2在“E”和“M”细胞类型决定及神经外胚层细胞“编程”与“重编程”中的作用；进而通过比较人胚胎干细胞“E”和过表达Lhx2人胚胎干细胞“M”两者间的表观遗传图谱，提炼“E”和“M”的特异表观标记，解析出Lhx2通过表观遗传学实现“E”-“M”转换的调控网络；并研究这一调控网络在人胚胎干细胞定向分化为神经外胚层细胞以及人成纤维细胞直接转分化为神经外胚层细胞中的关键作用。

中文关键词： 编程；重编程；Lhx2；上皮间质转换；神经外胚层

英文摘要： The transition in between epithelial and mesenchymal cell types accompanies the cell fate determining processes when pluripotent stem cells are programmed to three germ layers or somatic cells are reprogrammed back into pluripotency. However, it is still unclear whether epithelial-mesenchymal transition (EMT) or mesenchymal-epithelial transition (MET) is required for cell fate conversion during programming or reprogramming. Moreover, the determining factors for EMT or MET still needs to be defined. According to our preliminary data, transcription factor Lhx2 strongly induces EMT in human embryonic stem cells and this EMT is a prerequisite for proper differentiation of human neuroectoderm. In this application, we will first investigate the role of Lhx2 in determining the epithelial and mesenchymal fates as well as its role in neuroectoderm programming and reprogramming. By comparison of normal human embryonic stem cells (“E” type) and Lhx2 overexpressed human embryonic stem cells (“M” type), epigenetic landscapes related to “E” and “M” fates will be drawn by studying DNA and histone modifications. By comparison of Lhx2 binding sites and specific epigenetic modifications related to “E” and “M”, molecular mechanisms underlying Lhx2 regulated EMT will be studied extensively. We will also try to investigate the funct

英文关键词： Programming；Reprogramming；Lhx2；EMT；Neuroectoderm