Bourc'his D, Bestor T H
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Cytogenet Genome Res. 2006;113(1-4):36-40. doi: 10.1159/000090813.
Roughly equal numbers of imprinted genes are subject to repression from alleles of maternal and of paternal origin. This masks the strong sexual dimorphism that underlies major aspects of imprinted gene regulation. First, imprints are established very early in the male germ line and persist for the reproductive life of the organism, while maternal genomic imprints are established shortly prior to ovulation and are erased soon thereafter in the primordial germ cells of the next generation. Second, many CpG island-associated promoters are subject to maternal methylation but no known promoters are subject to paternal-specific germline methylation. The few known paternal methylation marks are kilobases distant from the affected genes and have a low CpG density. Third, Dnmt3L is required for imprint establishment but not transposon methylation in female germ cells, while Dnmt3L is required for transposon methylation and has only a minor role in de novo methylation at imprinted loci in male germ cells. Fourth, maternally expressed genes are commonly repressed on the paternal allele by paternally expressed imprinted genes produced in cis and encoding nontranslated RNAs. It is here suggested that rapid loss of highly mutable methylated CpG sites has led to the depletion of methylation target sites in paternally repressed imprinted genes, and that an imprinting mechanism based on RNAs or local inhibitory influences of ongoing transcription of regulatory loci has evolved to counter the erosion of paternally methylated regulatory regions. This mutability model is based on the fact that paternally methylated sequences are maintained in the methylated state for a much longer time than are maternally methylated sequences, and are therefore lost at a correspondingly faster rate. The difference in timing of imprint establishment is likely to underlie the increasing sexual dimorphism of other aspects of imprinted gene expression.
来自母本和父本的等位基因受到抑制的印记基因数量大致相等。这掩盖了印记基因调控主要方面所基于的强烈的性别二态性。首先，印记在雄性生殖系中很早就建立起来，并在生物体的生殖寿命中持续存在，而母本基因组印记在排卵前不久建立，并在下一代的原始生殖细胞中很快被消除。其次，许多与CpG岛相关的启动子会发生母本甲基化，但没有已知的启动子会发生父本特异性的种系甲基化。少数已知的父本甲基化标记与受影响的基因相距数千碱基，且CpG密度较低。第三，Dnmt3L是雌性生殖细胞中印记建立所必需的，但不是转座子甲基化所必需的，而Dnmt3L是转座子甲基化所必需的，在雄性生殖细胞的印记位点从头甲基化中只起次要作用。第四，母本表达的基因通常在父本等位基因上被顺式产生并编码非翻译RNA的父本表达的印记基因所抑制。这里提出，高度可变的甲基化CpG位点的快速丢失导致了父本抑制的印记基因中甲基化靶位点的耗尽，并且基于RNA或调控位点正在进行的转录的局部抑制影响的印记机制已经进化，以对抗父本甲基化调控区域的侵蚀。这种突变模型基于这样一个事实，即父本甲基化序列比母本甲基化序列在甲基化状态下维持的时间长得多，因此相应地以更快的速度丢失。印记建立时间的差异可能是印记基因表达其他方面日益增加的性别二态性的基础。
