Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer.
Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer.
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先天性生长障碍和癌症中IGF2-H19基因座的明显甲基化变化。
DOI：
10.1371/journal.pone.0001849
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发表时间：
2008-03-26
期刊：
影响因子：
3.7
通讯作者：
Riccio A
中科院分区：
文献类型：
--
作者：
Murrell A;Ito Y;Verde G;Huddleston J;Woodfine K;Silengo MC;Spreafico F;Perotti D;De Crescenzo A;Sparago A;Cerrato F;Riccio A
差异甲基化区域（DMR）与许多印记基因相关。在小鼠中，H19基因上游DMR（称为印记控制区（IC 1））的甲基化在雄性生殖系中获得，并通过长程相互作用影响邻近胰岛素样生长因子2（Igf 2）基因中100 kb以外DMR的甲基化状态。在人类中，IC 1处的种系来源或合子后获得的印迹缺陷与IGF 2的异常激活或抑制相关，分别导致先天性生长障碍Beckwith-Wiedemann（BWS）和Silver-Russell（SRS）综合征。在肾母细胞瘤和结直肠癌中，已经观察到IGF 2的双等位基因表达与IGF 2中DMR处的甲基化丧失相关。该DMR，称为DMR 0，已被证明在沉默的母体IGF 2等位基因上甲基化，推测其在抑制中起作用。IGF 2 DMR 0甲基化变化在BWS或SRS病因学中的作用尚不清楚。我们通过传统的亚硫酸氢盐测序和焦磷酸测序分析了BWS、SRS和Wilms肿瘤患者中DMR 0的甲基化状态。我们在这里表明，与以前的报道相反，IGF 2 DMR 0实际上是在外周血和肾脏中活跃的父亲等位基因上甲基化的。这与IC 1甲基化状态相似，并且与提出的母体IGF 2等位基因的沉默功能不一致。具有IC 1甲基化缺陷的Beckwith-Wiedemann和Silver-Russell患者在IGF 2 DMR 0处具有相似的甲基化缺陷，与IC 1顺式调节IGF 2甲基化一致。然而，在肾母细胞瘤中，IC 1和IGF 2 DMR 0的甲基化谱表明甲基化变化发生在两个亲本等位基因上，而不是顺式。这些结果支持了一个模型，其中DMR 0和IC 1具有相反的易感性，全球高甲基化和低甲基化在肿瘤发生过程中，独立于父母的起源印记。相反，在胚胎发生期间，DMR 0根据在IC 1处的生殖系甲基化印记被甲基化或去甲基化，这表明在肿瘤和非肿瘤细胞中印记丢失的不同机制。
Differentially methylated regions (DMRs) are associated with many imprinted genes. In mice methylation at a DMR upstream of the H19 gene known as the Imprint Control region (IC1) is acquired in the male germline and influences the methylation status of DMRs 100 kb away in the adjacent Insulin-like growth factor 2 (Igf2) gene through long-range interactions. In humans, germline-derived or post-zygotically acquired imprinting defects at IC1 are associated with aberrant activation or repression of IGF2, resulting in the congenital growth disorders Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, respectively. In Wilms tumour and colorectal cancer, biallelic expression of IGF2 has been observed in association with loss of methylation at a DMR in IGF2. This DMR, known as DMR0, has been shown to be methylated on the silent maternal IGF2 allele presumably with a role in repression. The effect of IGF2 DMR0 methylation changes in the aetiology of BWS or SRS is unknown. We analysed the methylation status of the DMR0 in BWS, SRS and Wilms tumour patients by conventional bisulphite sequencing and pyrosequencing. We show here that, contrary to previous reports, the IGF2 DMR0 is actually methylated on the active paternal allele in peripheral blood and kidney. This is similar to the IC1 methylation status and is inconsistent with the proposed silencing function of the maternal IGF2 allele. Beckwith-Wiedemann and Silver-Russell patients with IC1 methylation defects have similar methylation defects at the IGF2 DMR0, consistent with IC1 regulating methylation at IGF2 in cis. In Wilms tumour, however, methylation profiles of IC1 and IGF2 DMR0 are indicative of methylation changes occurring on both parental alleles rather than in cis. These results support a model in which DMR0 and IC1 have opposite susceptibilities to global hyper and hypomethylation during tumorigenesis independent of the parent of origin imprint. In contrast, during embryogenesis DMR0 is methylated or demethylated according to the germline methylation imprint at the IC1, indicating different mechanisms of imprinting loss in neoplastic and non-neoplastic cells.
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影响因子：
5.3
作者：
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通讯作者：
Ohlsson, R
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30.8
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