TET3 in Terminal Erythroid Differentiation

TET3 在红细胞终末分化中的作用

• 批准号: 9016542
• 负责人: Xiuli An
• 金额: $ 29.18万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9016542
• 关键词: Aberrant DNA Methylation; Anemia; Biology; Bone Marrow; CD34 gene; Cell Culture System; Cell Differentiation process; Complex; Congenital dyserythropoietic anemia; Cooley' s anemia; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; Development; Diamond-Blackfan anemia; Disease; Dysmyelopoietic Syndromes; Enzymes; Epigenetic Process; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Event; Excision; Future; Genes; Growth; Health; Hematological Disease; Human; Knockout Mice; Lead; Mediating; Methods; Methylation; Modification; Molecular; Mus; Myeloid Cells; Myeloproliferative disease; Oocytes; Play; Population; Positioning Attribute; Process; Production; Protein Family; Protein translocation; Regulation; Regulatory Pathway; Research; Research Project Grants; Role; Spleen; Subfamily lentivirinae; Testing; Time; base; bone marrow failure syndrome; cytokine; demethylation; embryonic stem cell; erythroid differentiation; global health; improved; in vivo; insight; knock-down; methyl group; novel; self-renewal; small hairpin RNA; transcription factor; transcriptome sequencing

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.

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。

项目成果

Stabilization of F-actin by tropomyosin isoforms regulates the morphology and mechanical behavior of red blood cells.

原肌球蛋白亚型对 F-肌动蛋白的稳定作用可调节红细胞的形态和机械行为。

• DOI: 10.1091/mbc.e16-10-0699
• 发表时间: 2017
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Sui,Zhenhua;Gokhin,DavidS;Nowak,RobertaB;Guo,Xinhua;An,Xiuli;Fowler,VeliaM
• 通讯作者: Fowler,VeliaM

SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: implications for understanding of ineffective erythropoiesis in MDS.

SF3B1 缺陷通过激活 p53 通路损害人类红细胞生成：对理解 MDS 无效红细胞生成的影响

• DOI: 10.1186/s13045-018-0558-8
• 发表时间: 2018-02-12
• 期刊: Journal of hematology & oncology
• 影响因子: 28.5
• 作者: Huang Y;Hale J;Wang Y;Li W;Zhang S;Zhang J;Zhao H;Guo X;Liu J;Yan H;Yazdanbakhsh K;Huang G;Hillyer CD;Mohandas N;Chen L;Sun L;An X
• 通讯作者: An X