转录因子KLFs调控干细胞红系分化的分子网络机制

项目名称： 转录因子KLFs调控干细胞红系分化的分子网络机制

项目编号： No.31471115

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 方向东

作者单位： 中国科学院北京基因组研究所

项目金额： 88万元

中文摘要： 干细胞定向分化是当前干细胞与再生医学领域的研究热点，而造血干细胞的红系分化是其中重要的课题之一。在以往研究工作中，作为重要转录因子的KLFs家族多个成员已被证实参与干细胞的红系分化。然而，在造血干细胞定向红系分化过程中，KLFs家族多因子的分子网络调控机制尚不清楚。KLF1是已经被广泛研究的红系分化因子；KLF9、KLF15是项目组前期工作中新确定的潜在调控红系分化的重要因子。初步研究提示，KLF9、KLF15和KLF1参与构成的分子网络在造血干细胞定向红系分化过程中具有重要作用。本研究将利用人脐带血来源的造血干细胞定向红系分化的细胞模型，分析3种KLFs的异常表达对造血干细胞定向红系分化的影响，初步明确在红系分化过程中存在KLFs分子作用网络。再通过对高通量转录组学和表观基因组学数据的整合分析，构建以KLFs为核心的红系分化调控网络。结合生物功能实验，探讨该网络调控红系分化的分子机制。

中文关键词： 造血干细胞；红细胞分化；分子网络；高通量测序；细胞模型

英文摘要： Currently, directional differentiation of stem cells is the hot spot in the field of regenerative medicine and stem cell research, and erythroid differentiation of hematopoietic stem cells is one of the important topics. Previous studies have indicated that the majority of KLFs family members participate in erythroid differentiation of stem cells. However, the mechanisms by which KLF family network regulates erythroid differentiation of hematopoietic stem cells are still poorly understood. Extensive studies have demonstrated KLF1 to be an erythroid differentiation factor, whereas previous work in our lab identified KLF9 and KLF15 as potential novel erythroid differentiation factors. Preliminary studies indicate that the molecular network comprising of KLF9, KLF15 and KLF1 potentially plays critical roles in erythroid differentiation of hematopoietic stem cells. In this project, we intend to employ hematopoietic stem cells (CD34+CD38-) from human cord blood, which can differentiate and develop into erythrocytes, as the primary cell model. We plan to investigate the effects of manipulated expression of these three KLFs (knockdown and overexpression) on erythropoiesis, in order to demonstrate the presence of KLF network during erythropoiesis. Through integrating the transcriptomics and epigenetics high-through sequencing data, we intend to build up KLF regulatory network for erythroid differentiation of hematopoietic stem cells. Finally, we will explore the molecular mechanism by which the constructed KLF network regulates erythroid differentiation by performing biological experiments using cell model.

英文关键词： hematopoietic stem cells;erythroid differentiation;molecular networks;high-throughput sequencing;cell model