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

TY - JOUR

T1 - GATA-1 Inhibits PU.1 Gene via DNA and Histone H3K9 Methylation of Its Distal Enhancer in Erythroleukemia

AU - Burda, Pavel

AU - Vargova, Jarmila

AU - Curik, Nikola

AU - Salek, Cyril

AU - Papadopoulos, Giorgio Lucio

AU - Strouboulis, John

AU - Stopka, Tomas

PY - 2016/3/24

Y1 - 2016/3/24

N2 - 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.

AB - 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.

KW - Cell Differentiation/genetics

KW - DNA (Cytosine-5-)-Methyltransferase 1

KW - DNA (Cytosine-5-)-Methyltransferases/genetics

KW - DNA Methylation/genetics

KW - Enhancer Elements, Genetic

KW - GATA1 Transcription Factor/genetics

KW - Gene Expression Regulation, Leukemic

KW - Histones/genetics

KW - Humans

KW - Leukemia, Erythroblastic, Acute/genetics

KW - Leukemia, Myeloid, Acute/genetics

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - Proto-Oncogene Proteins/biosynthesis

KW - Trans-Activators/biosynthesis

KW - Transcription, Genetic

U2 - 10.1371/journal.pone.0152234

DO - 10.1371/journal.pone.0152234

M3 - Article

C2 - 27010793

SN - 1932-6203

VL - 11

SP - e0152234

JO - PLoS ONE

JF - PLoS ONE

IS - 3

ER -