Ciccone David N, Su Hui, Hevi Sarah, Gay Frédérique, Lei Hong, Bajko Jeffrey, Xu Guoliang, Li En, Chen Taiping
Epigenetics Program, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Nature. 2009 Sep 17;461(7262):415-8. doi: 10.1038/nature08315. Epub 2009 Sep 2.
Differential DNA methylation of the paternal and maternal alleles regulates the parental origin-specific expression of imprinted genes in mammals. The methylation imprints are established in male and female germ cells during gametogenesis, and the de novo DNA methyltransferase DNMT3A and its cofactor DNMT3L are required in this process. However, the mechanisms underlying locus- and parental-specific targeting of the de novo DNA methylation machinery in germline imprinting are poorly understood. Here we show that amine oxidase (flavin-containing) domain 1 (AOF1), a protein related to the lysine demethylase KDM1 (also known as LSD1), functions as a histone H3 lysine 4 (H3K4) demethylase and is required for de novo DNA methylation of some imprinted genes in oocytes. AOF1, now renamed lysine demethylase 1B (KDM1B) following a new nomenclature, is highly expressed in growing oocytes where genomic imprints are established. Targeted disruption of the gene encoding KDM1B had no effect on mouse development and oogenesis. However, oocytes from KDM1B-deficient females showed a substantial increase in H3K4 methylation and failed to set up the DNA methylation marks at four out of seven imprinted genes examined. Embryos derived from these oocytes showed biallelic expression or biallelic suppression of the affected genes and died before mid-gestation. Our results suggest that demethylation of H3K4 is critical for establishing the DNA methylation imprints during oogenesis.
父本和母本等位基因的差异性DNA甲基化调控着哺乳动物中印迹基因的亲本来源特异性表达。甲基化印记在配子发生过程中的雄性和雌性生殖细胞中建立，在此过程中需要从头DNA甲基转移酶DNMT3A及其辅因子DNMT3L。然而，在种系印记中，从头DNA甲基化机制的位点特异性和亲本特异性靶向的潜在机制仍知之甚少。在这里，我们表明，胺氧化酶（含黄素）结构域1（AOF1），一种与赖氨酸去甲基化酶KDM1（也称为LSD1）相关的蛋白质，作为组蛋白H3赖氨酸4（H3K4）去甲基化酶发挥作用，并且是卵母细胞中一些印记基因从头DNA甲基化所必需的。AOF1，在采用新命名法后现更名为赖氨酸去甲基化酶1B（KDM1B），在建立基因组印记生长中的卵母细胞中高度表达。靶向破坏编码KDM1B的基因对小鼠发育和卵子发生没有影响。然而，来自KDM1B缺陷雌性的卵母细胞显示H3K4甲基化大幅增加，并且在所检测的七个印记基因中的四个上未能建立DNA甲基化标记。来自这些卵母细胞的胚胎显示受影响基因的双等位基因表达或双等位基因抑制，并在妊娠中期前死亡。我们的结果表明，H3K4去甲基化对于卵母细胞发生过程中建立DNA甲基化印记至关重要。
