title: GATA-1 Inhibits PU.1 Gene via DNA and Histone H3K9 Methylation of Its Distal Enhancer in Erythroleukemia.
abstract: GATA-1 and PU.1 are two important hematopoietic transcription factors that mutually inhibit each other in progenitor cells to guide entrance into the erythroid or myeloid lineage, respectively. PU.1 controls its own expression during myelopoiesis by binding to the distal URE enhancer, whose deletion leads to acute myeloid leukemia (AML). We herein present evidence that GATA-1 binds to the PU.1 gene and inhibits its expression in human AML-erythroleukemias (EL). Furthermore, GATA-1 together with DNA methyl Transferase I (DNMT1) mediate repression of the PU.1 gene through the URE. Repression of the PU.1 gene involves both DNA methylation at the URE and its histone H3 lysine-K9 methylation and deacetylation as well as the H3K27 methylation at additional DNA elements and the promoter. The GATA-1-mediated inhibition of PU.1 gene transcription in human AML-EL mediated through the URE represents important mechanism that contributes to PU.1 downregulation and leukemogenesis that is sensitive to DNA demethylation therapy.
authors.affiliation: Biocev and Pathological Physiology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.|Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Burda
authors.affiliation: Biocev and Pathological Physiology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Vargova
authors.affiliation: Biocev and Pathological Physiology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.|Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Nikola
authors.initials: N
authors.lastname: Curik
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Cyril
authors.initials: C
authors.lastname: Salek
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Heraklion, Crete, Greece.|Department of Biology, University of Crete, Heraklion, Crete, Greece.
authors.forename: Giorgio Lucio
authors.initials: GL
authors.lastname: Papadopoulos
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Heraklion, Crete, Greece.
authors.forename: John
authors.initials: J
authors.lastname: Strouboulis
authors.affiliation: Biocev and Pathological Physiology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.|1st Medical Department-Hematology, General Faculty Hospital, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Stopka
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004742:Enhancer Elements, Genetic; D050982:GATA1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006657:Histones / Q000235:genetics; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D050982:GATA1 Transcription Factor; D006657:Histones; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494688:GATA1 protein, human; C000619380:DNMT1 protein, human