Aberrant activation of the TAL1/SCL gene has been involved in majority of T cell acute lymphoblastic leukemia (T-ALL). As a hematopoietic-specific basic helix-loop-helix transcription factor, TAL1 is essential for hematopoietic stem cell renewal and lineage development during normal hematopoiesis. Given its relevance to normal hematopoiesis and T-ALL, understanding the transcriptional control of this transcription factor will elucidate the molecular mechanisms underlying the control of normal hematopoiesis and leukemogenesis. Several lines of evidence have established that TAL1 associates with transcriptional coactivators and corepressors which differentially affect TAL1's function in erythroid differentiation. Hence, we hypothesize that histone modifying enzymes regulate TAL1-mediated transcriptional control during hematopoiesis and their misregulations would contribute to the development of T-cell leukemia. In this application, we focus on investigating how the opposite histone modifying enzymes that we have identified as TAL1-associated cofactors regulate TAL1 function in hematopoiesis and leukemogenesis.
The specific aims of this research proposal are: 1) Elucidate the biological function of histone demethylase in the control of TAL1-mediated transcription and hematopoiesis;2) Analyze the role of histone methyltransferase in TAL1-mediated transcriptional regulation during erythroid differentiation;3) Understand the molecular basis of histone modifying enzymes in TAL1-induced normal hematopoiesis and leukemogenesis. By completing the proposed research, we expect to further understand how TAL1- directed transcriptional activity contributes to normal hematopoiesis and leukemic transformation. We will also gain knowledge on the role of TAL1-associated histone modifying enzymes in these processes. This information will eventually help to design new therapeutic approaches to treat leukemia. Moreover, the study will shed light on the control of transcription factors on hematopoietic stem cell growth and differentiation. Project Narative: Transcription factor TAL1/SCL is critical for the formation of normal blood cells and is frequently associated with a specific form of leukemia, T cell acute lymphoblastic leukemia (T-ALL) which is a malignant disease with very few effective treatments. In this proposal, we will explore how TAL1 regulates the formation of blood cells and the development of leukemia. These studies will provide novel insights into TAL1 function in the regulation of blood cell development and will help to design new therapeutic approaches to treat leukemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090589-05
Application #
8294533
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mitchell, Phyllis
Project Start
2008-08-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$351,079
Indirect Cost
$103,579
Name
University of Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Stees, Jared R; Hossain, Mir A; Sunose, Tomoki et al. (2016) High Fractional Occupancy of a Tandem Maf Recognition Element and Its Role in Long-Range ?-Globin Gene Regulation. Mol Cell Biol 36:238-50
Yang, H; Yan, B; Liao, D et al. (2015) Acetylation of HDAC1 and degradation of SIRT1 form a positive feedback loop to regulate p53 acetylation during heat-shock stress. Cell Death Dis 6:e1747
Salz, Tal; Deng, Changwang; Pampo, Christine et al. (2015) Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer. Mol Cancer Res 13:461-9
Tusi, Betsabeh Khoramian; Deng, Changwang; Salz, Tal et al. (2015) Setd1a regulates progenitor B-cell-to-precursor B-cell development through histone H3 lysine 4 trimethylation and Ig heavy-chain rearrangement. FASEB J 29:1505-15
Li, Xuehui; Yang, Hui; Huang, Suming et al. (2014) Histone deacetylase 1 and p300 can directly associate with chromatin and compete for binding in a mutually exclusive manner. PLoS One 9:e94523
Patel, B; Kang, Y; Cui, K et al. (2014) Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia. Leukemia 28:349-61
Salz, Tal; Li, Guangyao; Kaye, Frederic et al. (2014) hSETD1A regulates Wnt target genes and controls tumor growth of colorectal cancer cells. Cancer Res 74:775-86
Yang, Hui; Salz, Tal; Zajac-Kaye, Maria et al. (2014) Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators. FASEB J 28:4265-79
Barrow, Joeva J; Li, Ying; Hossain, Mir et al. (2014) Dissecting the function of the adult ?-globin downstream promoter region using an artificial zinc finger DNA-binding domain. Nucleic Acids Res 42:4363-74
Liu, Li; Souto, Joseph; Liao, Wenbin et al. (2013) Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells. J Biol Chem 288:34719-28

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