Cell-Autonomous Function of Runx1 Transcriptionally Regulates Mouse Megakaryocytic MaturationReport as inadecuate




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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.



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

Source: http://plos.srce.hr/



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