Transcription elongation factor S-II is required for definitive hematopoiesis
Transcription elongation factor S-II is required for definitive hematopoiesis
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DOI：
10.1128/mcb.26.8.3194-3203.2006
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发表时间：
2006-04-01
影响因子：
5.3
通讯作者：
Sekimizu, K
中科院分区：
文献类型：
--
作者：
Ito, T;Arimitsu, N;Sekimizu, K
转录延伸因子S-II/TFIIS在体外通过刺激核糖核酸聚合酶11的新生核糖核酸裂解活性促进转录片段的通读。然而，S-H功能在高等真核生物中的生物学意义尚不清楚。为了确定它在哺乳动物发育中的作用，我们通过靶向基因破坏产生了S-II缺陷小鼠。纯合子零突变体在妊娠中期死亡，面色苍白，表明患有严重贫血。S-II-/-胚胎外周血中确定的红细胞数量减少，并干扰了胎肝的红细胞分化。S-II-/-胎肝细胞凋亡率显著增加，与Bclx(L)基因表达下调相一致。在S-II-/-胎肝中存在表型识别的造血干细胞和体外集落形成造血祖细胞，表明S-II对于造血干细胞的生成和分化是必不可少的。然而，S-II缺陷胎肝细胞移植到致死照射的成年小鼠体内后，表现出长期再生能力的丧失，这表明S-II缺陷导致了造血干细胞自我更新的内在缺陷。因此，S-II在最终的造血过程中具有关键的和非多余的作用。
Transcription elongation factor S-II/TFIIS promotes readthrough of transcriptional blocks by stimulating nascent RNA cleavage activity of RNA polymerase 11 in vitro. The biologic significance of S-H function in higher eukaryotes, however, remains unclear. To determine its role in mammalian development, we generated S-II-deficient mice through targeted gene disruption. Homozygous null mutants died at midgestation with marked pallor, suggesting severe anemia. S-II-/- embryos had a decreased number of definitive erythrocytes in the peripheral blood and disturbed erythroblast differentiation in fetal liver. There was a dramatic increase in apoptotic cells in S-II-/- fetal liver, which was consistent with a reduction in Bcl-x(L), gene expression. The presence of phenotypically defined hematopoietic stem cells and in vitro colony-forming hematopoietic progenitors in S-II-/- fetal liver indicates that S-II is dispensable for the generation and differentiation of hematopoietic stem cells. S-II-deficient fetal liver cells, however, exhibited a loss of long-term repopulating potential when transplanted into lethally irradiated adult mice, indicating that S-II deficiency causes an intrinsic defect in the self-renewal of hematopoietic stem cells. Thus, S-II has critical and nonredundant roles in definitive hematopoiesis.