The human retinoblastoma gene is imprinted.
The human retinoblastoma gene is imprinted.
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DOI：
10.1371/journal.pgen.1000790
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发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
Buiting K
中科院分区：
文献类型：
--
作者：
Kanber D;Berulava T;Ammerpohl O;Mitter D;Richter J;Siebert R;Horsthemke B;Lohmann D;Buiting K
基因组印迹是一种表观遗传过程，导致亲本特有的DNA甲基化和基因表达。到目前为止，已知有∼60印记的人类基因。基于对一例多重印迹缺陷患者的全基因组甲基化分析，我们在13号染色体上的视网膜母细胞瘤基因内含子2中发现了一个差异甲基化的CpG岛。该CpG岛是源于9号染色体上KIAA0649基因的5‘-截短加工假基因的一部分，对应于祖先基因开放阅读框架中的两个小CpG岛。KIAA0649假基因位于22号染色体上，两个CpG岛已经退化，CpG二核苷酸完全甲基化。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等位基因RB1的转录水平，我们发现CpG岛的差异甲基化使RB1基因的表达偏向于母亲的等位基因。因此，RB1与CDKN1C的印迹方向相同，CDKN1C在RB1上游工作。同一途径的两个成分的印记表明，母体抑制细胞增殖存在很强的进化选择。基因组印迹是一种表观遗传过程，导致亲本特有的DNA甲基化和基因表达。这一过程中的缺陷会导致不正常的发育、生长或行为。目前尚不清楚印记为什么和如何进化，以及有多少人类基因被印记。基于对一例全身性印迹缺陷患者的全基因组DNA甲基化分析，我们发现13号染色体上的聚集性视网膜母细胞瘤1(RB1)基因是印迹的。RB1的印记与从9号染色体上的基因逆转录转座获得的DNA序列的插入有关。插入的DNA序列的一部分已进化成差异甲基化的替代RB1启动子。该序列的差异甲基化使RB1基因的表达偏向于母体等位基因。施加在RB1基因上的印记方向与母体表达的CDKN1C基因的方向相同，CDKN1C基因工作在RB1的上游。同一途径的两个成分的印记表明，母体抑制细胞增殖存在很强的进化选择。
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. Genomic imprinting is an epigenetic process leading to parent-of-origin–specific DNA methylation and gene expression. Defects in this process lead to abnormal development, growth, or behavior. It is still unclear why and how imprinting evolved and how many human genes are imprinted. Based on genome-wide DNA methylation analysis in a patient with a generalized imprinting defect, we have found that the paradigmatic retinoblastoma 1 (RB1) gene on chromosome 13 is imprinted. Imprinting of RB1 is linked to the insertion of a DNA sequence derived by retrotransposition from a gene on chromosome 9. Part of the inserted DNA sequence has evolved into a differentially methylated alternative RB1 promoter. Differential methylation of this sequence skews expression of the RB1 gene in favour of the maternal allele. The direction of the imprint imposed on the RB1 gene is the same as of the maternally expressed CDKN1C gene, 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.
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