PARENTAL-ORIGIN-SPECIFIC EPIGENETIC MODIFICATION OF THE MOUSE H19 GENE
PARENTAL-ORIGIN-SPECIFIC EPIGENETIC MODIFICATION OF THE MOUSE H19 GENE
复制标题
DOI：
10.1038/362751a0
复制
发表时间：
1993-04-22
期刊：
影响因子：
64.8
通讯作者：
SURANI, MA
中科院分区：
文献类型：
--
作者：
FERGUSONSMITH, AC;SASAKI, H;SURANI, MA
H19基因在正常胚胎中产生大量功能未知的发育调节转录物1。在小鼠中，它位于7号染色体上，并受到亲本印记的转录调控，这导致母系遗传基因表达和父系遗传基因被抑制2。因此，携带远端7号染色体（MatDi 7）3的母本重复/父本缺陷的胚胎表达双倍剂量的H19。在这里，我们研究了父母的起源特异性表观遗传修饰，可能参与这种调节比较CpG甲基化和核酸酶的敏感性MatDi 7胚胎与正常的同窝出生。我们发现，在CpG岛启动子和基因的5'部分的特定位点甲基化，只有在父亲的等位基因。此外，MatDi 7胚胎染色质中的活跃的母系等位基因对核酸酶更敏感和更容易接近。因此，H19启动子区域的超甲基化和染色质致密化与该基因的父系遗传拷贝的抑制有关。大多数，但不是全部，这些位点在精子中是未甲基化的，在受精后发生父本启动子的甲基化。这些结果与我们对编码胰岛素样生长因子II的紧密连锁和印迹基因的发现形成对比（参考文献4）。
THE H19 gene produces an abundant developmentally regulated transcript of unknown function in normal embryos1. In the mouse it lies on chromosome 7 and is subject to transcriptional regulation by parental imprinting, which results in the maternally inherited gene being expressed and the paternally inherited gene being repressed2. Embryos carrying maternal duplication/paternal deficiency for distal chromosome 7 (MatDi7)3 therefore express a double dose of H19. Here we examine the parental-origin-specific epigenetic modifications that may be involved in this regulation by comparing CpG methylation and nuclease sensitivity of chromatin in MatDi7 embryos with normal littermates. We show that specific sites in the CpG island promoter and 5' portion of the gene are methylated only on the paternal allele. Furthermore, active maternal alleles in chromatin of MatDi7 embryos are more sensitive and accessible to nucleases. Therefore hypermethylation and chromatin compaction in the region of the H19 promoter is associated with repression of the paternally inherited copy of the gene. Most, but not all, of these sites are unmethylated in sperm, with methylation of the paternal promoter occurring after fertilization. These results contrast with our findings for the closely linked and reciprocally imprinted gene encoding insulin-like growth factor II (ref. 4).