Erythroid differentiation of adult hematopoietic progenitor cells requires stimulation by erythropoietin, a hypoxia inducible cytokine that promotes erythroid progenitor cell survival, proliferation, differentiation and hemoglobin production. Erythropoietin binds to its cell surface receptor and induces transcription factors that regulate erythroid gene expression such as the general erythroid transcription factor GATA-1, the basic helix-loop-helix transcription factor, TAL1, and EKLF which is relatively specific for beta-globin expression. Erythropoietin stimulated induction of erythroid transcription factors also activates expression of the erythropoietin receptor that results in increased sensitivity to erythropoietin. DNA binding of TAL1 is required for normal erythropoiesis and we found that TAL1 regulates erythropoietin receptor expression mediated via three conserved E-box binding motifs (CAGCTG) in the erythropoietin receptor 5 untranslated transcribed region. TAL1 increases association of the GATA-1/TAL1/LMO2/Ldb1 transcription activation complex to the region that includes the transcription start site and the 5 GATA and 3 E-box motifs flanking the erythropoietin receptor transcription start site. In erythroid progenitor cells with high expression of erythropoietin receptor, TAL1 binds to the flanking 5 GATA and 3 E-box regions of the erythropoietin receptor promoter and nucleosome phasing shifts to increase the linker region containing the erythropoietin receptor transcription start site and. These data suggest that TAL1 binds to the promoter region contributing to activation of the erythropoietin receptor expression. Forced expression of TAL1 increases erythropoietin receptor expression leading to increased sensitivity to erythropoietin and provides a mechanism contributing to cell expansion during erythropoietin stimulated erythropoiesis.

Project Start
Project End
Budget Start
Budget End
Support Year
37
Fiscal Year
2012
Total Cost
$362,920
Indirect Cost
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Subotički, Tijana; Mitrović Ajtić, Olivera; Beleslin-Čokić, Bojana B et al. (2016) Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms. Mol Carcinog :
Wright, Daniel G; Wright, Elizabeth C; Narva, Andrew S et al. (2015) Association of Erythropoietin Dose and Route of Administration with Clinical Outcomes for Patients on Hemodialysis in the United States. Clin J Am Soc Nephrol 10:1822-30
Čokić, Vladan P; Mossuz, Pascal; Han, Jing et al. (2015) Microarray and Proteomic Analyses of Myeloproliferative Neoplasms with a Highlight on the mTOR Signaling Pathway. PLoS One 10:e0135463
Gammella, Elena; Diaz, Victor; Recalcati, Stefania et al. (2015) Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly. Am J Physiol Regul Integr Comp Physiol 308:R330-5
Wang, Xunde; Mendelsohn, Laurel; Rogers, Heather et al. (2014) Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Krüppel-like factor. Blood 124:946-54
Park, Ji Won; Piknova, Barbora; Huang, Paul L et al. (2013) Effect of blood nitrite and nitrate levels on murine platelet function. PLoS One 8:e55699
Cokic, Vladan P; Smith, Reginald D; Biancotto, Angelique et al. (2013) Globin gene expression in correlation with G protein-related genes during erythroid differentiation. BMC Genomics 14:116
Yang, Tao; Jian, Wei; Luo, Yi et al. (2012) Acetylation of histone deacetylase 1 regulates NuRD corepressor complex activity. J Biol Chem 287:40279-91
Cokic, Vladan P; Bhattacharya, Bhaskar; Beleslin-Cokic, Bojana B et al. (2012) JAK-STAT and AKT pathway-coupled genes in erythroid progenitor cells through ontogeny. J Transl Med 10:116
Hu, Xin; Li, Xingguo; Valverde, Kristell et al. (2009) LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. Proc Natl Acad Sci U S A 106:10141-6

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