Umlauf David, Goto Yuji, Cao Ru, Cerqueira Frédérique, Wagschal Alexandre, Zhang Yi, Feil Robert
Institute of Molecular Genetics, CNRS UMR-5535 and University of Montpellier-II, 1919, route de Mende, 34090 Montpellier, France.
Nat Genet. 2004 Dec;36(12):1296-300. doi: 10.1038/ng1467. Epub 2004 Oct 31.
Imprinted genes are clustered in domains, and their allelic repression is mediated by imprinting control regions. These imprinting control regions are marked by DNA methylation, which is essential to maintain imprinting in the embryo. To explore how imprinting is regulated in placenta, we studied the Kcnq1 domain on mouse distal chromosome 7. This large domain is controlled by an intronic imprinting control region and comprises multiple genes that are imprinted in placenta, without the involvement of promoter DNA methylation. We found that the paternal repression along the domain involves acquisition of trimethylation at Lys27 and dimethylation at Lys9 of histone H3. Eed-Ezh2 Polycomb complexes are recruited to the paternal chromosome and potentially regulate its repressive histone methylation. Studies on embryonic stem cells and early embryos support our proposal that chromatin repression is established early in development and is maintained in the placenta. In the embryo, however, imprinting is stably maintained only at genes that have promoter DNA methylation. These data underscore the importance of histone methylation in placental imprinting and identify mechanistic similarities with X-chromosome inactivation in extraembryonic tissues, suggesting that the two epigenetic mechanisms are evolutionarily linked.
印记基因在结构域中聚集，其等位基因抑制由印记控制区域介导。这些印记控制区域由DNA甲基化标记，这对于在胚胎中维持印记至关重要。为了探究胎盘印记是如何被调控的，我们研究了小鼠7号远端染色体上的Kcnq1结构域。这个大结构域由一个内含子印记控制区域控制，包含多个在胎盘中被印记的基因，且不涉及启动子DNA甲基化。我们发现沿着该结构域的父本抑制涉及组蛋白H3赖氨酸27的三甲基化和赖氨酸9的二甲基化。Eed-Ezh2多梳复合体被招募到父本染色体上，并可能调控其抑制性组蛋白甲基化。对胚胎干细胞和早期胚胎的研究支持了我们的观点，即染色质抑制在发育早期建立并在胎盘中维持。然而，在胚胎中，印记仅在具有启动子DNA甲基化的基因上稳定维持。这些数据强调了组蛋白甲基化在胎盘印记中的重要性，并确定了与胚外组织中X染色体失活的机制相似性，表明这两种表观遗传机制在进化上是相关的。
