红系发育是由多潜能造血干细胞增殖、分化成红细胞的过程，需要精细复杂调控。DNA甲基化/去甲基化调控很多生理过程，但它在红系发育过程中的作用却少有研究。本课题组前期发现在人类红系发育过程中出现全基因组去甲基化。DNA去甲基化是由TET家族调控。TET家族成员TET2在红系细胞中表达。骨髓增生异常综合症（MDS）患者红系发育异常，TET2突变是MDS患者中最常见的突变。我们在前期工作中对TET2在红系发育中的作用进行了研究，发现敲低人类CD34+细胞中的TET2导致红系细胞的过度增殖、分化延迟及分化晚期凋亡增加。而这些表型变化与MDS患者红系发育异常类似。由此我们推测，TET2对正常红系发育起着重要的调控作用，TET2突变与MDS中异常红系发育有关。本项目将深入探讨TET2对红系发育的调控机制。该研究不仅为红系研究提供新视野，还有助于阐明MDS患者红系发育异常机制，为 MDS的诊疗提供新策略。

Erythropoiesis is a process by which multipotent hematopoietic stem cells proliferate, differentiate and eventually form mature erythrocytes. It is a complex process that requires tight regulation. Although it is well established that DNA methylation/demethylation influences many biologic processes, its role in erythropoiesis remains largely unexplored. We and others have recently documented that global demethylation occurs during human erythropoiesis. DNA demethylation is mediated by Ten-eleven-translocation (TET) family members. TET2 is expressed in erythroid cells. Mutation of TET2 is the most common mutation in MDS patients. MDS patients have abnormal erythropoiesis. To explore the role of TET2 in DNA demethylation and human erythropoiesis, we knocked down TET2 by shRNA in human CD34+ cells and found that TET2 knockdown resulted in hyper-proliferation of erythroid cells, delayed erythroid differentiation, increased apoptosis of late stage erythroblasts. Interestingly, these changes are characteristics of altered erythropoiesis in myelodysplasticsyndroms (MDS) patients. Based on these findings, we hypothesize that TET2 plays important roles during normal erythropoiesis and that mutation of TET2 in MDS is associated with altered erythropoiesis in MDS. In this application, we will explore the mechanisms by which TET2 regulates erythropoiesis by examining the effects of TET2 knockdown or TET2 mutation on genome wide gene expression and DNA methylation/demethylation. Successful accomplishment of proposed studies will not only provide novel insights into erythroid biology but also help in developing mechanistic understanding of disordered erythropoiesis in MDS.