DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes
DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes
复制标题
DOI：
10.1101/gad.1640708
复制
发表时间：
2008-04-01
影响因子：
10.5
通讯作者：
Nakano, Toru
中科院分区：
文献类型：
--
作者：
Kuramochi-Miyagawa, Satomi;Watanabe, Toshiaki;Nakano, Toru
转座元件的沉默发生在雄性胎儿配子体发生过程中，通过其调控区域的DNA甲基化发生。果蝇piwi的两个小鼠同源基因MILI （miwi-like）和MIWI2（小鼠piwi - 2）的缺失通过损害反转录转座子调控区域的DNA甲基化来激活反转录转座子基因的表达。然而，由于尚不清楚突变体中的DNA甲基化缺陷是否由于新生DNA甲基化损伤，我们分析了野生型，MILI-null和MIWI2-null男性胎儿生殖细胞中的DNA甲基化和piwi相互作用小RNA （piRNA）表达。我们发现，在mili缺失和miwi2缺失的男性生殖细胞中，Line-1（长分散核元件）和IAP（胞内A粒子）逆转录转座子的调控区域的DNA甲基化缺陷发生在从头甲基化水平上。综合分析表明，胎儿生殖细胞的pirna与先前在新生儿和成人生殖细胞中发现的pirna不同。在MILI-和miwi2 -缺失条件下，胎儿生殖细胞中pirna的表达减少，尽管两种突变体之间的减少程度有显著差异。我们的数据强烈表明，MILI和MIWI2在胎儿男性生殖细胞中建立逆转录转座子的从头DNA甲基化中起重要作用。
Silencing of transposable elements occurs during fetal gametogenesis in males via de novo DNA methylation of their regulatory regions. The loss of MILI (miwi-like) and MIWI2 (mouse piwi 2), two mouse homologs of Drosophila Piwi, activates retrotransposon gene expression by impairing DNA methylation in the regulatory regions of the retrotransposons. However, as it is unclear whether the defective DNA methylation in the mutants is due to the impairment of de novo DNA methylation, we analyze DNA methylation and Piwi-interacting small RNA (piRNA) expression in wild-type, MILI-null, and MIWI2-null male fetal germ cells. We reveal that defective DNA methylation of the regulatory regions of the Line-1 (long interspersed nuclear elements) and IAP (intracisternal A particle) retrotransposons in the MILI-null and MIWI2-null male germ cells takes place at the level of de novo methylation. Comprehensive analysis shows that the piRNAs of fetal germ cells are distinct from those previously identified in neonatal and adult germ cells. The expression of piRNAs is reduced under MILI- and MIWI2-null conditions in fetal germ cells, although the extent of the reduction differs significantly between the two mutants. Our data strongly suggest that MILI and MIWI2 play essential roles in establishing de novo DNA methylation of retrotransposons in fetal male germ cells.