Astuti D, Latif F, Wagner K, Gentle D, Cooper W N, Catchpoole D, Grundy R, Ferguson-Smith A C, Maher E R
Department of Paediatrics and Child Health, Section of Medical and Molecular Genetics, University of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK.
Br J Cancer. 2005 Apr 25;92(8):1574-80. doi: 10.1038/sj.bjc.6602478.
Epigenetic alterations in the 11p15.5 imprinted gene cluster are frequent in human cancers and are associated with disordered imprinting of insulin-like growth factor (IGF)2 and H19. Recently, an imprinted gene cluster at 14q32 has been defined and includes two closely linked but reciprocally imprinted genes, DLK1 and GTL2, that have similarities to IGF2 and H19, respectively. Both GTL2 and H19 are maternally expressed RNAs with no protein product and display paternal allele promoter region methylation, and DLK1 and IGF2 are both paternally expressed. To determine whether methylation alterations within the 14q32 imprinted domain occur in human tumorigenesis, we investigated the status of the GTL2 promoter differentially methylated region (DMR) in 20 neuroblastoma tumours, 20 phaeochromocytomas and, 40 Wilms' tumours. Hypermethylation of the GTL2 promoter DMR was detected in 25% of neuroblastomas, 10% of phaeochromocytoma and 2.5% of Wilms' tumours. Tumours with GTL2 promoter DMR hypermethylation also demonstrated hypermethylation at an upstream intergenic DMR thought to represent a germline imprinting control element. Analysis of neuroblastoma cell lines revealed that GTL2 DMR hypermethylation was associated with transcriptional repression of GTL2. These epigenetic findings are similar to those reported in Wilms' tumours in which H19 repression and DMR hypermethylation is associated with loss of imprinting (LOI, biallelic expression) of IGF2. However, a neuroblastoma cell line with hypermethylation of the GTL2 promoter and intergenic DMR did not show LOI of DLK1 and although treatment with a demethylating agent restored GTL2 expression and reduced DLK1 expression. As described for IGF2/H19, epigenetic changes at DLK1/GTL2 occur in human cancers. However, these changes are not associated with DLK1 LOI highlighting differences in the imprinting control mechanisms operating in the IGF2-H19 and DLK1-GTL2 domains. GTL2 promoter and intergenic DMR hypermethylation is associated with the loss of GTL2 expression and this may contribute to tumorigenesis in a subset of human cancers.
11p15.5印记基因簇的表观遗传改变在人类癌症中很常见，并且与胰岛素样生长因子（IGF）2和H19的印记紊乱有关。最近，已确定14q32处的一个印记基因簇，其中包括两个紧密连锁但相互印记的基因DLK1和GTL2，它们分别与IGF2和H19相似。GTL2和H19都是母系表达的RNA，没有蛋白质产物，并且显示父本等位基因启动子区域甲基化，而DLK1和IGF2都是父系表达的。为了确定14q32印记区域内的甲基化改变是否发生在人类肿瘤发生过程中，我们研究了20例神经母细胞瘤、20例嗜铬细胞瘤和40例肾母细胞瘤中GTL2启动子差异甲基化区域（DMR）的状态。在25%的神经母细胞瘤、10%的嗜铬细胞瘤和2.5%的肾母细胞瘤中检测到GTL2启动子DMR的高甲基化。具有GTL2启动子DMR高甲基化的肿瘤在上游基因间DMR处也表现出高甲基化，该区域被认为代表种系印记控制元件。对神经母细胞瘤细胞系的分析表明，GTL2 DMR高甲基化与GTL2的转录抑制有关。这些表观遗传学发现与肾母细胞瘤中报道的相似，其中H19抑制和DMR高甲基化与IGF2的印记丢失（LOI，双等位基因表达）有关。然而，一个具有GTL2启动子和基因间DMR高甲基化的神经母细胞瘤细胞系并未显示DLK1的LOI，尽管用去甲基化剂处理可恢复GTL2表达并降低DLK1表达。如IGF2/H19所述，DLK1/GTL2处的表观遗传变化发生在人类癌症中。然而，这些变化与DLK LOI无关，这突出了在IGF2 - H19和DLK1 - GTL2区域中运作的印记控制机制的差异。GTL2启动子和基因间DMR高甲基化与GTL2表达的丧失有关，这可能在一部分人类癌症的肿瘤发生中起作用。
Zotero 插件
