Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19104-6148, USA.
Mamm Genome. 2009 Sep-Oct;20(9-10):532-43. doi: 10.1007/s00335-009-9225-2. Epub 2009 Sep 16.
Imprinted genes are epigenetically regulated so that only one allele is expressed in a parent-of-origin-dependent manner. Although they represent a small subset of the mammalian genome, imprinted genes are essential for normal development. The regulatory mechanisms underlying imprinting are complex and have been the subject of extensive investigation. DNA methylation is the best-established epigenetic mark that is critical for the allele-specific expression of imprinted genes. This mark must be correctly established in the germline, maintained throughout life, and erased and reestablished in the germline the next generation. These events coincide with the genome-wide epigenetic reprogramming that occurs during gametogenesis and early embryogenesis; therefore, the establishment and maintenance of DNA methylation must be tightly regulated. Studies on enzymes that participate in both de novo methylation and its maintenance (i.e., the DNMT family) have provided information on how methylation influences imprinting. However, many aspects of the regulation of DNA methylation are unknown, including how methylation complexes are targeted and the molecular mechanisms underlying DNA demethylation. In this review we focus on the epigenetic changes that occur in the germline and early embryo, with an emphasis on imprinting. We summarize recent findings on factors influencing DNA methylation establishment, maintenance, and erasure that have further elucidated the mechanisms of imprinting, while highlighting topics that require further investigation.
印迹基因通过表观遗传调控，使得只有一个等位基因以亲本来源依赖的方式表达。尽管它们只占哺乳动物基因组的一小部分，但印迹基因对于正常发育是必不可少的。印迹的调控机制非常复杂，已经成为广泛研究的课题。DNA 甲基化是最成熟的表观遗传标记，对于印迹基因的等位基因特异性表达至关重要。这种标记必须在生殖细胞中正确建立，在整个生命周期中维持，并在下一代生殖细胞中被抹去和重新建立。这些事件与配子发生和早期胚胎发生过程中发生的全基因组表观遗传重编程同时发生；因此，DNA 甲基化的建立和维持必须受到严格调控。参与从头甲基化及其维持的酶（即 DNMT 家族）的研究提供了关于甲基化如何影响印迹的信息。然而，DNA 甲基化调控的许多方面仍不清楚，包括甲基化复合物如何靶向以及 DNA 去甲基化的分子机制。在这篇综述中，我们重点讨论了生殖细胞和早期胚胎中发生的表观遗传变化，特别强调了印迹。我们总结了最近关于影响 DNA 甲基化建立、维持和抹去的因素的发现，这些发现进一步阐明了印迹的机制，同时突出了需要进一步研究的主题。
