TET3 in Terminal Erythroid Differentiation

描述(由申请人提供)：我们项目的长期目标是对正常和疾病状态下的终末红系分化的调节有一个全面的机械理解。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疾病的一个特征，这是一个主要的全球健康问题。尽管进行了大量的努力，但对终末红系分化的调节机制的了解仍远未完成。过去对红细胞生成调控的研究主要集中在生长因子、细胞因子和转录因子方面。由于红细胞生成是一个复杂的过程，需要严格的监管，因此 重要的是探索其他机制对红细胞生成的调节。DNA的甲基化状态影响包括细胞分化在内的许多生物过程。最近的研究证实了Tet蛋白介导的5-羟甲基胞嘧啶的产生和DNA去甲基化在细胞分化中的重要作用。这项应用侧重于了解红系终末分化过程中整体去甲基化的潜在分子机制，以及这一事件在红系生物学中的功能，重点是TET3。我们预计，拟议研究的成功完成将有助于从总体上更好地了解红系细胞的发育和分化。具体地说，我们希望我们提出的研究将验证新发现的红系生物学中新发现的表观遗传调控途径，并为未来高影响力的研究努力提供基础。由于DNA甲基化异常是许多血液病的基础，包括骨髓增生异常综合征的红细胞生成障碍，我们的发现可能也会为这些疾病提供新的见解。

DESCRIPTION (provided by applicant): 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.