T-cell acute leukemia 1 (TAL1) regulation of erythropoietin receptor and association with excessive erythrocytosis.

Abstract

During erythropoiesis, erythropoietin stimulates induction of erythroid transcription factors that activate expression of erythroid genes including the erythropoietin receptor (EPO-R) that results in increased sensitivity to erythropoietin. DNA binding of the basic helix-loop-helix transcription factor, TAL1/SCL, is required for normal erythropoiesis. A link between elevated TAL1 and excessive erythrocytosis is suggested by erythroid progenitor cells from a patient that exhibits unusually high sensitivity to erythropoietin with concomitantly elevated TAL1 and EPO-R expression. We found that TAL1 regulates EPO-R expression mediated via three conserved E-box binding motifs (CAGCTG) in the EPO-R 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 EPO-R transcription start site suggesting that TAL1 promotes accessibility of this region. Nucleosome shifting has been demonstrated to facilitate TAL1 but not GATA-1 binding to regulate target gene expression. Accordingly, we observed that with induced expression of EPO-R in hemotopoietic progenitor cells, nucleosome phasing shifts to increase the linker region containing the EPO-R transcription start site and TAL1 binds to the flanking 5' GATA and 3' E-box regions of the promoter. These data suggest that TAL1 binds to the EPO-R promoter to activate EPO-R expression and provides a potential link to elevated EPO-R expression leading to hypersensitivity to erythropoietin and the resultant excessive erythrocytosis.

• Authors: Heather Rogers, Li Wang, Xiaobing Yu, Mawadda Alnaeeli, Kairong Cui, Keji Zhao, James J Bieker, Josef Prchal, Suming Huang, Babette Weksler, Constance Tom Noguchi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 44 Pg. 36720-31 (Oct 26 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22982397 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antigens, CD
• Basic Helix-Loop-Helix Transcription Factors
• EPO protein, human
• GATA1 Transcription Factor
• GATA1 protein, human
• GATA2 Transcription Factor
• GATA2 protein, human
• Kruppel-Like Transcription Factors
• Proto-Oncogene Proteins
• Receptors, Erythropoietin
• T-Cell Acute Lymphocytic Leukemia Protein 1
• beta-Globins
• erythroid Kruppel-like factor
• Erythropoietin
• TAL1 protein, human
• Luciferases, Renilla
• JAK2 protein, human
• Janus Kinase 2

Topics

• Adult
• Antigens, CD (metabolism)
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Binding Sites
• Case-Control Studies
• Cell Differentiation
• Cell Proliferation
• Cells, Cultured
• DNA Mutational Analysis
• Erythroid Cells (metabolism)
• Erythropoietin (physiology)
• GATA1 Transcription Factor (genetics, metabolism)
• GATA2 Transcription Factor (genetics, metabolism)
• Gene Expression
• Gene Expression Regulation
• Genes, Reporter
• Hematopoietic Stem Cells (metabolism)
• Humans
• Janus Kinase 2 (genetics)
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Luciferases, Renilla (biosynthesis, genetics)
• Male
• Mutation, Missense
• Polycythemia (genetics, metabolism, pathology)
• Promoter Regions, Genetic
• Protein Binding
• Proto-Oncogene Proteins (metabolism)
• Receptors, Erythropoietin (genetics, metabolism)
• T-Cell Acute Lymphocytic Leukemia Protein 1
• beta-Globins (genetics, metabolism)