内源性逆转录病毒在小鼠胚胎干细胞中的转录抑制机制

项目名称： 内源性逆转录病毒在小鼠胚胎干细胞中的转录抑制机制

项目编号： No.31671352

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 吕鑫屹

作者单位： 南开大学

项目金额： 25万元

中文摘要： 转座元件中的内源性逆转录病毒（ERV）是哺乳动物基因组的重要组成部分。大多数ERV的表达在细胞中被沉默，但少数ERV却在病变的细胞中被激活。胚胎干细胞（ES细胞）可以沉默多种ERV和逆转录病毒，因此在ES细胞中研究ERV的沉默机制可以使我们进一步了解干细胞基因组稳定性的维持、逆转录病毒的潜伏与疾病的发展机理。ES细胞抑制ERV I/II与ERV III的表观机制不同。我们对ES细胞如何通过转录调控不同ERV家族的沉默，从而导致不同的表观遗传抑制机理却知之甚少。因此在此项目中，我们将进行小规模的shRNA筛选以找到在小鼠ES细胞中分别调控ERV I/II与ERV III的关键转录调控因子，研究候选因子对ES细胞的分化潜能及多能性的退出的影响，探究候选因子对ERV及下游基因表达的调控机制，鉴定候选因子所处的蛋白调控网络，并最终揭示ERV I/II与ERV III在ES细胞中表达抑制机制。

中文关键词： 动物；反转录转座子；功能分析；表型；胚胎干细胞

英文摘要： Endogenous retrovirus (ERV), a class of transposable elements, is an important component of mammalian genome. Most of ERVs are slienced in cells, but some of them are activated in diseased cells, such as cancer cells. Embryonic stem cells (ES cells) could silence different groups of ERVs, as well as exogenous retrovirus. Therefore, studying the mechanism of ERV silencing in ES cells will facilitate us to further understand the maintenance of ES cell genome stability, mechanism used by retrovirus to remain dormant, and the development of cancer. ERVs are classified into three groups: ERV I, ERV II and ERV III. There is still lack of knowledge about how transcriptional regulators repress different ERV families in ES cells and how this leads to distinct epigenetic silencing mechanisms. Therefore, we propose to (1) carry out a small-scale shRNA screen to identify transcriptional repressors of ERV I/II or ERV III in mouse ES cells, (2) study the role of candidate repressors in regulating ES cell pluripotency maintenance and pluripotency dissolution, (3) probe the mechanism of candidate factor in regulating downstream ERVs' and genes' expression, (4) characterize the protein interaction networks of candidate factors and eventually reveal the mechanistic differences and similarities between repression of ERV I/II and ERV III in ES cells.

英文关键词： animal;retrotransposon;functional analysis;phenotype;embryonic stem cells