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The Human Retinoblastoma Gene Is Imprinted

机译：人类视网膜母细胞瘤基因被印记

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Genomic imprinting is an epigenetic process leading to parent-of-origin–specific DNA methylation and gene expression. To date, ～60 imprinted human genes are known. Based on genome-wide methylation analysis of a patient with multiple imprinting defects, we have identified a differentially methylated CpG island in intron 2 of the retinoblastoma (RB1) gene on chromosome 13. The CpG island is part of a 5′-truncated, processed pseudogene derived from the KIAA0649 gene on chromosome 9 and corresponds to two small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In four other KIAA0649 pseudogene copies, which are located on chromosome 22, the two CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analysing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2′-deoxycytidine–treated lymphoblastoid cells, we have found that differential methylation of the CpG island skews RB1 gene expression in favor of the maternal allele. Thus, RB1 is imprinted in the same direction as CDKN1C, which operates upstream of RB1. The imprinting of two components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation.
机译：基因组印记是一种表观遗传过程，导致起源于母体的特定DNA甲基化和基因表达。迄今为止，已知约有60种印迹的人类基因。基于对具有多个烙印缺陷的患者的全基因组甲基化分析，我们在染色体13的视网膜母细胞瘤（RB1）基因的内含子2中鉴定出差异甲基化的CpG岛。该CpG岛是5'截短，经过加工的一部分来源于9号染色体上的KIAA0649基因的假基因，对应于祖先基因开放阅读框中的两个小CpG岛。它在母亲染色体13上被甲基化，并充当父亲染色体13上另一种RB1转录的弱启动子。在位于染色体22上的其他四个KIAA0649假基因拷贝中，两个CpG岛已经退化，CpG二核苷酸是完全甲基化。通过分析血细胞以及高甲基化和5-氮杂-2'-脱氧胞苷处理的淋巴母细胞中的等位基因RB1转录水平，我们发现CpG岛的差异甲基化使RB1基因表达偏向于母亲等位基因。因此，RB1的印记方向与CDKN1C相同，CDKN1C在RB1的上游运行。同一途径的两个组成部分的印记表明，对母体抑制细胞增殖有很强的进化选择。

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