title: Cell-autonomous function of Runx1 transcriptionally regulates mouse megakaryocytic maturation.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Niv
authors.initials: N
authors.lastname: Pencovich
authors.forename: Ram
authors.initials: R
authors.lastname: Jaschek
authors.forename: Joseph
authors.initials: J
authors.lastname: Dicken
authors.forename: Ayelet
authors.initials: A
authors.lastname: Amit
authors.forename: Joseph
authors.initials: J
authors.lastname: Lotem
authors.forename: Amos
authors.initials: A
authors.lastname: Tanay
authors.forename: Yoram
authors.initials: Y
authors.lastname: Groner
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D005786:Gene Expression Regulation; D008533:Megakaryocytes / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; D050880:p300-CBP Transcription Factors