Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation
Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation
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DOI：
10.1101/gad.13.20.2691
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发表时间：
1999-10-15
影响因子：
10.5
通讯作者：
Sauvageau, G
中科院分区：
文献类型：
--
作者：
Lessard, J;Schumacher, A;Sauvageau, G
小鼠Polycomb-Group （PcG）蛋白Fed和Bmi1通过片段特异性抑制Hox基因表达来控制胚胎发育过程中的轴向模式。这两种蛋白参与不同的多聚体复合物，被认为使用一种共同的分子机制，使Hox和其他下游靶基因的调控区域无法进入转录激活因子。除了轴向模式外，Bmi1还参与造血，因为一个功能缺失的等位基因会导致骨髓祖细胞的严重减少。在这里，有证据表明eed和Bmi1在造血细胞增殖中的拮抗作用是一致的。eed零等位基因的杂合性导致明显的髓细胞和淋巴细胞增生缺陷，表明eed参与了淋巴细胞和髓细胞祖细胞池大小的负调控。eed的这种抗增殖功能似乎不是由Hox基因或肿瘤抑制基因座g16(INK4a)/p19（ARF）介导的，因为这些基因的表达在eed突变体中没有改变。eed与Bmi1突变小鼠的交叉实验表明，Bmi1在控制原始骨髓细胞增殖中具有上位性。然而，这两个基因之间的遗传相互作用是细胞类型特异性的，因为存在一个或两个突变的eed反式等位基因弥补了前b骨髓细胞中bmi1的缺乏。因此，这些研究表明造血细胞增殖是由抑制（含ed）和增强（含bmi1） PcG基因复合物的相对贡献调节的。
The murine Polycomb-Group (PcG) proteins Fed and Bmi1 govern axial patterning during embryonic development by segment-specific repression of Hox gene expression. The two proteins engage in distinct multimeric complexes that are thought to use a common molecular mechanism to render the regulatory regions of Hox and other downstream target genes inaccessible tot transcriptional activators. Beyond axial patterning, Bmi1 is also involved in hemopoiesis because a loss-of-function allele causes a profound decrease in bone marrow progenitor cells. Here, evidence is presented that is consistent with an antagonistic function of eed and Bmi1 in hemopoietic cell proliferation. Heterozygosity for an eed null allele causes marked myelo- and lymphoproliferative defects, indicating that eed is involved in the negative regulation of the pool size of lymphoid and myeloid progenitor cells. This antiproliferative function of eed does not appear to be mediated by Hox genes or the tumor suppressor locus g16(INK4a)/p19(ARF) because expression of these genes was not altered in eed mutants. Intercross experiments between eed and Bmi1 mutant mice revealed that Bmi1 is epistatic to eed in the control of primitive bone marrow cell proliferation. However, the genetic interaction between the two genes is cell-type specific as the presence of one or two mutant alleles of eed trans-complements the Bmi1-deficiency in pre-B bone marrow cells. These studies thus suggest that hemopoietic cell proliferation is regulated by the relative contribution of repressive (Eed-containing) and enhancing (Bmi1-containing) PcG gene complexes.