Journal Article

Cell-Autonomous Function of Runx1 Transcriptionally Regulates Mouse Megakaryocytic Maturation

Amit, Ayelet, Lotem, Joseph, Pencovich, Niv, Groner, Yoram, Jaschek, Ram, Dicken, Joseph, Tanay, Amos

2013

Overview

RUNX1 transcription factor (TF) is a key regulator of megakaryocytic development and when mutated is associated with familial platelet disorder and predisposition to acute myeloid leukemia (FPD-AML). We used mice lacking Runx1 specifically in megakaryocytes (MK) to characterized Runx1-mediated transcriptional program during advanced stages of MK differentiation. Gene expression and chromatin-immunoprecipitation-sequencing (ChIP-seq) of Runx1 and p300 identified functional Runx1 bound MK enhancers. Runx1/p300 co-bound regions showed significant enrichment in genes important for MK and platelet homeostasis. Runx1 occupied genomic regions were highly enriched in RUNX and ETS motifs and to a lesser extent in GATA motif. Megakaryocytic specificity of Runx1/P300 bound enhancers was validated by transfection mutagenesis and Runx1/P300 co-bound regions of two key megakaryocytic genes Nfe2 and Selp were tested by in vivo transgenesis. The data provides the first example of genome wide Runx1/p300 occupancy in maturating primary FL-MK, unravel the Runx1-regulated program controlling MK maturation in vivo and identify a subset of its bona fide regulated genes. It advances our understanding of the molecular events that upon RUNX1mutations in human lead to the predisposition to familial platelet disorders and FPD-AML.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acute myeloid leukemia / Animals / Applied mathematics / Base Sequence / Binding Sites / Biology / Blood platelets / Cell Differentiation / Cells, Cultured / Chromatin / Chromatin Immunoprecipitation / Computer science / Core Binding Factor Alpha 2 Subunit - physiology / Enhancers / ETS protein / Event-related potentials / Flat panel displays / Gene expression / Gene Expression Regulation / Gene sequencing / Genes / Genetic aspects / Genomes / Genomics / Homeostasis / Immunoprecipitation / Leukemia / Maturation / Medicine / Megakaryocytes / Megakaryocytes - physiology / Mice / Mice, Knockout / Mutagenesis / Mutation / Myeloid leukemia / p300-CBP Transcription Factors - metabolism / Platelets / Primary Cell Culture / Promoter Regions, Genetic / Protein Binding / Rodents / Runx1 protein / Sequence Analysis, DNA / Stem cells / Transcription (Genetics) / Transcription factors / Transcription, Genetic / Transfection