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.

Public Health Relevance

Abnormal production of red cells is a feature of a large number of human hematological disorders. These include: Cooley's anemia, malarial anemia, congenital dyserythropoietic anemia's (CDA), Diamond- Blackfan Anemia, and various bone marrow failure syndromes such as myelodysplasia. This research project proposes to develop improved understanding of red cell production in normal and diseased states. It is anticipated that the findings from these studies will lead to a better understanding of erythroid cell development and differentiation and provide insights into disordered red cell production in a number of human red cell disorders that are a major global health problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK100810-03
Application #
9016542
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Roy, Cindy
Project Start
2014-04-01
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
New York Blood Center
Department
Type
DUNS #
073271827
City
New York
State
NY
Country
United States
Zip Code
10065
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Wu, Xianfang; Dao Thi, Viet Loan; Huang, Yumin et al. (2018) Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell 172:423-438.e25
Han, Xu; Zhang, Jieying; Peng, Yuanliang et al. (2017) Unexpected role for p19INK4d in posttranscriptional regulation of GATA1 and modulation of human terminal erythropoiesis. Blood 129:226-237
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