title: 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.affiliation: Molecular Medicine Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1822, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Rogers
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Yu
authors.forename: Mawadda
authors.initials: M
authors.lastname: Alnaeeli
authors.forename: Kairong
authors.initials: K
authors.lastname: Cui
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.forename: James J
authors.initials: JJ
authors.lastname: Bieker
authors.forename: Josef
authors.initials: J
authors.lastname: Prchal
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D041905:Erythroid Cells / Q000378:metabolism; D004921:Erythropoietin / Q000502:physiology; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D053614:Janus Kinase 2; D051741:Kruppel-Like Transcription Factors; D049410:Luciferases, Renilla; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D055544:beta-Globins; C554270:EPO protein, human; C494688:GATA1 protein, human; C494711:GATA2 protein, human; C080774:erythroid Kruppel-like factor; C067143:TAL1 protein, human; C507924:JAK2 protein, human