TET3 in Terminal Erythroid Differentiation

项目总结： 我们项目的长期目标是从机制上全面理解 正常和疾病状态下红系终末分化的调节。这一点很重要，因为 无序或无效的红细胞生成是大量人类血液系统疾病的一个特征， 重大的全球健康问题。尽管进行了密集的努力，但对监管的机械性理解 红系终末分化仍远未完成。大鼠红细胞生成调控的研究进展 过去主要集中在生长因子、细胞因子和转录因子上。AS 红细胞生成是一个复杂的过程，需要严格的调控，探索其调控是很重要的 通过其他机制进行的红细胞生成。DNA的甲基化状态影响许多生物过程。 包括细胞分化。最近的研究证实了Tet蛋白介导的5-羟色胺的重要作用。 细胞分化中羟甲基胞嘧啶的产生和DNA去甲基化。此应用程序侧重于 理解末端整体去甲基化的潜在分子机制 红系分化和这一事件在红系生物学中的作用，重点是TET3。我们 预期成功完成拟议的研究将有助于更好地了解 红系细胞发育和分化的一般情况。具体地说，我们希望我们提出的研究 应在红系生物学中验证新发现的表观遗传调控途径并提供 为未来高影响力的研究工作奠定了基础。因为异常的DNA甲基化是许多 血液学疾病，包括骨髓增生异常综合征的红细胞生成障碍，很可能是我们的 这些发现也可能为这些疾病提供新的见解。

Project Summary: The long-term objective of our project is to develop a comprehensive mechanistic understanding of the regulation of terminal erythroid differentiation in normal and diseased states. This is important because disordered or ineffective erythropoiesis is a feature of a large number of human hematological disorders, a major global health problem. Despite intensive efforts, the mechanistic understanding of regulation of terminal erythroid differentiation remains far from complete. The studies on regulation of erythropoiesis in the past have been primarily focused on growth factors, cytokines and transcription factors. As erythropoiesis is a complex process that requires tight regulation, it is important to explore the regulation of erythropoiesis by other mechanisms. The methylation status of DNA influences many biologic processes including cell differentiation. Recent studies identified important roles of TET protein-mediated 5- hydroxymethylcytosine production and DNA demethylation in cell differentiation. This application focuses on understanding the underlying molecular mechanisms for the global demethylation during terminal erythroid differentiation and the function of this event in erythroid biology with a tight focus on TET3. We anticipate that successful accomplishment of the proposed studies will lead to a better understanding of erythroid cell development and differentiation in general. Specifically we expect that our proposed studies should validate the newly identified novel epigenetic regulatory pathway in erythroid biology and provide the basis for future high impact research endeavors. As aberrant DNA methylation underlies many hematological diseases including the dyserythropoiesis of myelodysplastic syndromes, it is likely that our findings may also provide novel insights into these diseases.