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.
Highlights
Hematopoietic differentiation is controlled by the interplay of opposing lineage-specific transcription factors: PU.1 and GATA-1
Immunofluorescence shows a partial overlap between GATA-1 and PU.1 signals (S2B Fig)
GATA-1 and PU.1 are co-expressed at similar level in the human acute myeloid leukemia (AML)-EL
Summary
Hematopoietic differentiation is controlled by the interplay of opposing lineage-specific transcription factors: PU. and GATA-1. If one of these factors predominates it leads to a specification of a particular lineage [1,2,3,4,5]. While deletion of the PU. gene completely abrogates myeloid and/or lymphoid development in mice, transgenic disruption of the upstream regulatory element (URE) results in ~80% reduction of PU. level and AML [1, 9]. Disruption of the URE by the integrated spleen focus forming provirus (SFFV) associates with the development of AML-EL [10, 11]. Mutations of PU. gene in human AML are sporadic and the epigenetic mechanisms regulating PU. level may be more important
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