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Sci Rep. 2016 Jul 26;6:30255. doi: 10.1038/srep30255.

NF-E2, FLI1 and RUNX1 collaborate at areas of dynamic chromatin to activate transcription in mature mouse megakaryocytes.

Zang C1,2, Luyten A2,3,4, Chen J2,3, Liu XS1,2, Shivdasani RA2,3,4,5.

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Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Department of Pediatric Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.


Mutations in mouse and human Nfe2, Fli1 and Runx1 cause thrombocytopenia. We applied genome-wide chromatin dynamics and ChIP-seq to determine these transcription factors' (TFs) activities in terminal megakaryocyte (MK) maturation. Enhancers with H3K4me2-marked nucleosome pairs were most enriched for NF-E2, FLI and RUNX sequence motifs, suggesting that this TF triad controls much of the late MK program. ChIP-seq revealed NF-E2 occupancy near previously implicated target genes, whose expression is compromised in Nfe2-null cells, and many other genes that become active late in MK differentiation. FLI and RUNX were also the motifs most enriched near NF-E2 binding sites and ChIP-seq implicated FLI1 and RUNX1 in activation of late MK, including NF-E2-dependent, genes. Histones showed limited activation in regions of single TF binding, while enhancers that bind NF-E2 and either RUNX1, FLI1 or both TFs gave the highest signals for TF occupancy and H3K4me2; these enhancers associated best with genes activated late in MK maturation. Thus, three essential TFs co-occupy late-acting cis-elements and show evidence for additive activity at genes responsible for platelet assembly and release. These findings provide a rich dataset of TF and chromatin dynamics in primary MK and explain why individual TF losses cause thrombopocytopenia.

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