Stochastic imprinting in the progeny of Dnmt3L-/- females
Stochastic imprinting in the progeny of Dnmt3L-/- females
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DOI：
10.1093/hmg/ddi475
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发表时间：
2006-02-15
影响因子：
3.5
通讯作者：
Kelsey, G
中科院分区：
文献类型：
--
作者：
Arnaud, P;Hata, K;Kelsey, G
印记基因的顺式作用调控序列受到种系特异性表观遗传修饰（印记）的影响，因此这类基因在后代中只从父系或母系等位基因表达。基因在种系中的差异标记在很大程度上仍有待阐明。虽然该标记的确切性质尚不完全清楚，但DNA甲基化[在差异甲基化区域（DMR）]似乎是一个主要的功能组分。最近在小鼠中的数据表明，Dnmt 3a，一种具有从头DNA甲基转移酶活性的酶，和相关蛋白Dnmt 3L是生殖细胞中印迹基因座甲基化所必需的。特别是母体甲基化印记，严格依赖于Dnmt 3L的存在。在这里，我们出乎意料地表明，甲基化印记可以存在于Dnmt 3L（-/-）雌性的一些后代中。这种Dnmt 3L缺陷对卵母细胞的影响的不完全突变既不是胚胎特异性的，也不是位点特异性的，而是随机的。我们确定，当它发生时，甲基化存在于胚胎和胚胎外组织中，并导致功能性印记。这表明这种母体甲基化直接或间接地从配子遗传。我们的研究结果表明，在没有Dnmt 3L的情况下，Dnmt 3a和其他可能的因子可以单独作用来标记个体DMR。然而，在所有位点建立适当的母体印记确实需要所有因素的组合。这一发现为进一步了解印迹相关疾病的发病机制和多态性印迹提供了依据。
The cis-acting regulatory sequences of imprinted genes are subject to germline-specific epigenetic modifications, the imprints, so that this class of genes is exclusively expressed from either the paternal or maternal allele in offspring. How genes are differentially marked in the germlines remains largely to be elucidated. Although the exact nature of the mark is not fully known, DNA methylation [at differentially methylated regions (DMRs)] appears to be a major, functional component. Recent data in mice indicate that Dnmt3a, an enzyme with de novo DNA methyltransferase activity, and the related protein Dnmt3L are required for methylation of imprinted loci in germ cells. Maternal methylation imprints, in particular, are strictly dependent on the presence of Dnmt3L. Here, we show that, unexpectedly, methylation imprints can be present in some progeny of Dnmt3L(-/-) females. This incomplete penetrance of the effect of Dnmt3L deficiency in oocytes is neither embryo nor locus specific, but stochastic. We establish that, when it occurs, methylation is present in both embryo and extra-embryonic tissues and results in a functional imprint. This suggests that this maternal methylation is inherited, directly or indirectly, from the gamete. Our results indicate that in the absence of Dnmt3L, factors such as Dnmt3a and possibly others can act alone to mark individual DMRs. However, establishment of appropriate maternal imprints at all loci does require a combination of all factors. This observation can provide a basis to understand mechanisms involved in some sporadic cases of imprinting-related diseases and polymorphic imprinting in human.