Steenman M J, Rainier S, Dobry C J, Grundy P, Horon I L, Feinberg A P
Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, 48109.
Nat Genet. 1994 Jul;7(3):433-9. doi: 10.1038/ng0794-433.
The insulin-like growth factor-II (IGF2) and H19 genes are imprinted in mouse and human, with expression of the paternal IGF2 and maternal H19 alleles. IGF2 undergoes loss of imprinting (LOI) in most Wilms' tumours (WT). We now show that: (i) LOI of IGF2 is associated with a 80-fold down regulation of H19 expression; (ii) these changes are associated with alterations in parental-origin-specific, tissue-independent sites of DNA methylation in the H19 promoter; and (iii) loss of heterozygosity is also associated with loss of H19 expression. Thus, imprinting of a large domain of the maternal chromosome results in a reversal to a paternal epigenotype. These data also suggest an epigenetic mechanism for inactivation of H19 as a tumour suppressor gene.
胰岛素样生长因子-II（IGF2）和H19基因在小鼠和人类中呈现印记现象，父本IGF2等位基因和母本H19等位基因表达。在大多数肾母细胞瘤（WT）中，IGF2会发生印记丢失（LOI）。我们现在发现：（i）IGF2的LOI与H19表达下调80倍相关；（ii）这些变化与H19启动子中亲本来源特异性、组织非依赖性DNA甲基化位点的改变有关；（iii）杂合性缺失也与H19表达缺失有关。因此，母本染色体一大区域的印记导致向父本表观基因型的逆转。这些数据还提示了一种将H19作为肿瘤抑制基因使其失活的表观遗传机制。
