GATA-1 Inhibits PU.1 Gene via DNA and Histone H3K9 Methylation of Its Distal Enhancer in Erythroleukemia

Pavel Burda, Jarmila Vargova, Nikola Curik, Cyril Salek, Giorgio Lucio Papadopoulos, John Strouboulis, Tomas Stopka

    Research output: Contribution to journalArticlepeer-review

    12 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)e0152234
    JournalPLoS ONE
    Volume11
    Issue number3
    DOIs
    Publication statusPublished - 24 Mar 2016

    Keywords

    • Cell Differentiation/genetics
    • DNA (Cytosine-5-)-Methyltransferase 1
    • DNA (Cytosine-5-)-Methyltransferases/genetics
    • DNA Methylation/genetics
    • Enhancer Elements, Genetic
    • GATA1 Transcription Factor/genetics
    • Gene Expression Regulation, Leukemic
    • Histones/genetics
    • Humans
    • Leukemia, Erythroblastic, Acute/genetics
    • Leukemia, Myeloid, Acute/genetics
    • Promoter Regions, Genetic
    • Protein Binding
    • Proto-Oncogene Proteins/biosynthesis
    • Trans-Activators/biosynthesis
    • Transcription, Genetic

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