Lewis Annabelle, Green Kelly, Dawson Claire, Redrup Lisa, Huynh Khanh D, Lee Jeannie T, Hemberger Myriam, Reik Wolf
Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, UK.
Development. 2006 Nov;133(21):4203-10. doi: 10.1242/dev.02612. Epub 2006 Oct 4.
The mouse Kcnq1 imprinted domain is located on distal chromosome 7 and contains several imprinted genes that are paternally repressed. Repression of these genes is regulated by a non-coding antisense transcript, Kcnq1ot1, which is paternally expressed. Maternal repression of Kcnq1ot1 is controlled by DNA methylation originating in the oocyte. Some genes in the region are imprinted only in the placenta, whereas others are imprinted in both extra-embryonic and embryonic lineages. Here, we show that Kcnq1ot1 is paternally expressed in preimplantation embryos from the two-cell stage, and that ubiquitously imprinted genes proximal to Kcnq1ot1 are already repressed in blastocysts, ES cells and TS cells. Repressive histone marks such as H3K27me3 are present on the paternal allele of these genes in both ES and TS cells. Placentally imprinted genes that are distal to Kcnq1ot1, by contrast, are not imprinted in blastocysts, ES or TS cells. In these genes, paternal silencing and differential histone marks arise during differentiation of the trophoblast lineage between E4.5 and E7.5. Our findings show that the dynamics during preimplantation development of gene inactivation and acquisition of repressive histone marks in ubiquitously imprinted genes of the Kcnq1 domain are very similar to those of imprinted X inactivation. By contrast, genes that are only imprinted in the placenta, while regulated by the same non-coding RNA transcript Kcnq1ot1, undergo epigenetic inactivation during differentiation of the trophoblast lineage. Our findings establish a model for how epigenetic gene silencing by non-coding RNA may depend on distance from the non-coding RNA and on lineage and differentiation specific factors.
小鼠Kcnq1印记域位于7号染色体远端，包含多个父本抑制的印记基因。这些基因的抑制由一个父本表达的非编码反义转录本Kcnq1ot1调控。Kcnq1ot1的母本抑制由源自卵母细胞的DNA甲基化控制。该区域的一些基因仅在胎盘中印记，而其他基因在胚外和胚内谱系中均有印记。在此，我们表明Kcnq1ot1在二细胞期的植入前胚胎中父本表达，并且Kcnq1ot1近端的普遍印记基因在囊胚、胚胎干细胞和滋养层干细胞中已经被抑制。在胚胎干细胞和滋养层干细胞中，这些基因的父本等位基因上都存在抑制性组蛋白标记，如H3K27me3。相比之下，Kcnq1ot1远端的胎盘印记基因在囊胚、胚胎干细胞或滋养层干细胞中没有印记。在这些基因中，父本沉默和组蛋白标记差异在E4.5至E7.5期间滋养层谱系分化过程中出现。我们的研究结果表明，Kcnq1域普遍印记基因在植入前发育过程中基因失活和获得抑制性组蛋白标记的动态过程与印记X染色体失活非常相似。相比之下，仅在胎盘中印记的基因，虽然受相同的非编码RNA转录本Kcnq1ot1调控，但在滋养层谱系分化过程中经历表观遗传失活。我们的研究结果建立了一个模型，说明非编码RNA介导的表观遗传基因沉默如何可能取决于与非编码RNA的距离以及谱系和分化特异性因子。
