title: NF-E2 p45 is important for establishing normal function of platelets.
abstract: 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(-/-):ΔNTD-Tg mice) displayed platelet hypofunction accompanied by mild thrombocytopenia. Furthermore, lung metastasis of melanoma cells, which requires platelet activation, was repressed in p45(-/-):ΔNTD-Tg mice compared to control mice, validating the impaired function of platelets produced from p45(-/-):ΔNTD-Tg megakaryocytes. By activating genes in megakaryocytes that mediate platelet production and function, p45 determines the quantity and quality of platelets.
authors: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Rie
authors: R
authors: Fujita
authors: Mariko
authors: M
authors: Takayama-Tsujimoto
authors: Hironori
authors: H
authors: Satoh
authors: Laura
authors: L
authors: Gutiérrez
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Satoshi
authors: S
authors: Fujii
authors: Akinori
authors: A
authors: Sarai
authors: Emery H
authors: EH
authors: Bresnick
authors: Masayuki
authors: M
authors: Yamamoto
authors: Hozumi
authors: H
authors: Motohashi
mesh_terms: D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000502:physiology*; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D015870:Gene Expression; D059014:High-Throughput Nucleotide Sequencing; D008175:Lung Neoplasms / Q000556:secondary; D008533:Megakaryocytes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000378:metabolism*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010974:Platelet Aggregation; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D059467:Transcriptome
chemical_list: D002843:Chromatin; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse
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