Dnmt3L and the establishment of maternal genomic imprints
Dnmt3L and the establishment of maternal genomic imprints
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DOI：
10.1126/science.1065848
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发表时间：
2001-12-21
期刊：
影响因子：
56.9
通讯作者：
Bestor, TH
中科院分区：
文献类型：
--
作者：
Bourc'his, D;Xu, GL;Bestor, TH
在一个称为基因组印记的过程中，雄性和雌性配子中互补的基因组在表观遗传上被沉默。Dnmt3L基因在配子发生期间在建立基因组印记的阶段表达。Dnmt3L的靶向破坏导致纯合子配偶无精子症，纯合子雌性的杂合子后代在妊娠中期前死亡。来自卵母细胞和胚胎的DNA的亚硫酸氢盐基因组测序表明，去除Dnmt 3L阻止了通常为母体甲基化的序列的甲基化。该缺陷是特定于印记区域的，并且全球基因组甲基化水平不受影响。在来自纯合突变卵母细胞的杂合胚胎中缺乏母体甲基化印记导致通常仅从父系来源的等位基因表达的基因的双等位基因表达。DNA胞嘧啶甲基转移酶的关键催化基序特征已经从Dnmt 3L中丢失，并且该蛋白质更可能充当印记建立的调节剂而不是DNA甲基转移酶。
Complementary sets of genes are epigenetically silenced in male and female gametes in a process termed genomic imprinting. The Dnmt3L gene is expressed during gametogenesis at stages where genomic imprints are established. Targeted disruption of Dnmt3L caused azoospermia in homozygous mates, and heterozygous progeny of homozygous, females died before midgestation. Bisulfite genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are normally maternally methylated. The defect was specific to imprinted regions, and global genome methylation levels were not affected. Lack of maternal methylation imprints in heterozygous embryos derived from homozygous mutant oocytes caused biallelic expression of genes that are normally expressed only from the allele of paternal origin. The key catalytic motifs characteristic of DNA cytosine methyltransferases have been lost from Dnmt3L, and the protein is more likely to act as a regulator of imprint establishment than as a DNA methyltransferase.