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

doi:10.1371/journal.pone.0152234

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

PLoS One. 2016 Mar 24;11(3):e0152234. doi: 10.1371/journal.pone.0152234. eCollection 2016.

Authors

Pavel Burda^{1

2}, Jarmila Vargova¹, Nikola Curik^{1

2}, Cyril Salek², Giorgio Lucio Papadopoulos^{3

4}, John Strouboulis³, Tomas Stopka^{1

5}

Affiliations

¹ Biocev and Pathological Physiology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.
² Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
³ Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Heraklion, Crete, Greece.
⁴ Department of Biology, University of Crete, Heraklion, Crete, Greece.
⁵ 1st Medical Department-Hematology, General Faculty Hospital, Prague, Czech Republic.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

GATA1 Transcription Factor
GATA1 protein, human
Histones
Proto-Oncogene Proteins
Trans-Activators
proto-oncogene protein Spi-1
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNMT1 protein, human

Grants and funding

Primary grant support: GACR P301/12/P380. Institutional: UNCE 204021, Prvouk-P24/LF1/3, SVV-2014-260033, CZ.1.05/1.1.00/02.0109, LQ1604 NPU II, 16-27790A, LH15170. GAUK-84314.