Bourc'his D, Xu G L, Lin C S, Bollman B, Bestor T H
Department of Genetics and Development, Transgenic Animal Facility, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Science. 2001 Dec 21;294(5551):2536-9. doi: 10.1126/science.1065848. Epub 2001 Nov 22.
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 males, 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.
在一个被称为基因组印记的过程中，互补的基因集在雄性和雌性配子中发生表观遗传沉默。Dnmt3L基因在配子发生过程中基因组印记建立的阶段表达。对Dnmt3L进行靶向破坏会导致纯合雄性无精子症，纯合雌性的杂合子后代在妊娠中期前死亡。对来自卵母细胞和胚胎的DNA进行亚硫酸氢盐基因组测序表明，去除Dnmt3L可阻止正常情况下由母体甲基化的序列发生甲基化。该缺陷是印记区域特有的，全基因组甲基化水平不受影响。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，导致通常仅从父本来源的等位基因表达的基因发生双等位基因表达。DNA胞嘧啶甲基转移酶特有的关键催化基序已从Dnmt3L中丢失，该蛋白更有可能作为印记建立的调节因子，而不是作为DNA甲基转移酶发挥作用。
