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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
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New York Blood Center
New York
United States
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Qu, Xiaoli; Zhang, Shijie; Wang, Shihui et al. (2018) TET2 deficiency leads to stem cell factor-dependent clonal expansion of dysfunctional erythroid progenitors. Blood 132:2406-2417
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
Sui, Zhenhua; Gokhin, David S; Nowak, Roberta B et al. (2017) Stabilization of F-actin by tropomyosin isoforms regulates the morphology and mechanical behavior of red blood cells. Mol Biol Cell 28:2531-2542
Yan, Hongxia; Wang, Yaomei; Qu, Xiaoli et al. (2017) Distinct roles for TET family proteins in regulating human erythropoiesis. Blood 129:2002-2012
Kats, Lev M; Proellocks, Nicholas I; Buckingham, Donna W et al. (2015) Interactions between Plasmodium falciparum skeleton-binding protein 1 and the membrane skeleton of malaria-infected red blood cells. Biochim Biophys Acta 1848:1619-1628
An, Xiuli; Schulz, Vincent P; Mohandas, Narla et al. (2015) Human and murine erythropoiesis. Curr Opin Hematol 22:206-11
Li, Jie; Hale, John; Bhagia, Pooja et al. (2014) Isolation and transcriptome analyses of human erythroid progenitors: BFU-E and CFU-E. Blood 124:3636-45