Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 33, Issue 14, Pages 2659-2670Publisher
TAYLOR & FRANCIS INC
DOI: 10.1128/MCB.01274-12
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Funding
- NIH [DK50107]
- NWO [863.09.012]
- JSPS
- MEXT
- Tohoku University Global COE for the Conquest of Signal Transduction Diseases with Network Medicine
- Core Research for Evolutional Science and Technology from the JST
- Tohoku University International Advanced Research and Education Organization
- Foundation for Promotion of Cancer Research (Japan)
- Princess Takamatsu Cancer Research Fund [09-24118]
- Grants-in-Aid for Scientific Research [24659142, 24390075] Funding Source: KAKEN
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NF-E2 is a heterodimeric transcription factor consisting of p45 and small Maf subunits. Since p45(-/-) mice display severe thrombocytopenia, p45 is recognized as a critical regulator of platelet production from megakaryocytes. To identify direct p45 target genes in megakaryocytes, we used chromatin immunoprecipitation (ChIP) sequencing to analyze the genome-wide chromatin occupancy of p45 in primary megakaryocytes. p45 target gene candidates obtained from the analysis are implicated in the production and function of platelets. Two of these genes, Selp and Myl9, were verified as direct p45 targets through multiple approaches. Since P-selectin, encoded by Selp, plays a critical role in platelet function during thrombogenesis, we tested whether p45 determines the intrinsic reactivity and potency of platelets generated from megakaryocytes. Mice expressing a hypomorphic p45 mutant instead of wild-type p45 in megakaryocytes (p45(-/-) :Delta NTD-Tg mice) displayed platelet hypofunction accompanied by mild thrombocytopenia. Furthermore, lung metastasis of melanoma cells, which requires platelet activation, was repressed in p45(-/-) :Delta NTD-Tg mice compared to control mice, validating the impaired function of platelets produced from p45(-/-): Delta NTD-Tg megakaryocytes. By activating genes in megakaryocytes that mediate platelet production and function, p45 determines the quantity and quality of platelets.
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