A role for E2F6 in the restriction of male-germ-cell-specific gene expression
A role for E2F6 in the restriction of male-germ-cell-specific gene expression
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DOI：
10.1016/j.cub.2005.04.060
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发表时间：
2005-06-07
期刊：
影响因子：
9.2
通讯作者：
Hagemeier, C
中科院分区：
文献类型：
--
作者：
Pohlers, M;Truss, M;Hagemeier, C
E2 F转录因子在细胞增殖的调节中起关键作用，并可细分为激活和抑制家族成员[1]。与其他E2 F一样，E2 F6与E2 F共有位点结合，但与E2 F1 -5相反，它缺乏Rb结合结构域，并作为Rb非依赖性转录阻遏物发挥作用[2-5]。相反，E2 F6已被证明与Polycomb（PcG）组蛋白复合[6，7]，其在基因沉默中具有公认的作用。在这里，我们发现E2 F6在基因表达的组织特异性中起着意想不到的重要作用。E2 F6缺陷小鼠普遍表达α-微管蛋白3和7基因，其在对照小鼠中严格地睾丸特异性表达。与我们鉴定的E2 F6靶基因Tex 12一样，微管蛋白3和7通常仅在雄性生殖细胞中表达。α-微管蛋白和Tex 12基因的启动子共享E2 F6结合的完全保守的E2 F位点。从机制上讲，E2 F6介导的抑制涉及CpG超甲基化锁定处于失活状态的靶启动子。因此，E2 F6对于某些雄性生殖细胞特异性基因的长期体细胞沉默是必不可少的，但它对于细胞周期调控是不可或缺的。
E2F transcription factors play a pivotal role in the regulation of cellular proliferation and can be subdivided into activating and repressing family members [1]. Like other E2Fs, E2F6 binds to E2F consensus sites, but in contrast to E2F1-5, it lacks an Rb binding domain and functions as an Rb-independent transcriptional repressor [2-5]. Instead, E2F6 has been shown to complex with Polycomb (PcG) group proteins [6, 7], which have a well-established role in gene silencing. Here, we show that E2F6 plays an unexpected and essential role in the tissue specificity of gene expression. E2F6-deficient mice ubiquitously express the a-tubulin 3 and 7 genes, which are expressed strictly testis-specifically in control mice. Like an additional E2F6 target gene, Tex12, that we identified, tubulin 3 and 7 are normally expressed in male germ cells only. The promoters of the a-tubulin and Tex12 genes share a perfectly conserved E2F site, which E2F6 binds to. Mechanistically, E2F6-mediated repression involves CpG hypermethylation locking target promoters in an inactive state. Thus, E2F6 is essential for the long-term somatic silencing of certain male-germ-cell-specific genes, but it is dispensable for cell-cycle regulation.