Prader-Willi综合征的整体甲基化和靶向印迹基因检测。

A. Manzardo, M. Butler
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引用次数: 5

摘要

在Prader-Willi综合征(PWS)中观察到的甲基化变化可能影响15号染色体上的印迹基因(顺式)或其他染色体上的其他印迹肥胖相关基因(反式)的整体甲基化和区域甲基化状态,从而导致影响PWS特有的肥胖表型的基因表达的差异效应。目的:在一组肥胖和非肥胖个体中,描述与肥胖表型相关的印迹型肥胖相关综合征(PWS)中选择的与肥胖表型相关的印迹基因的整体甲基化谱和甲基化状态。采用两种方法检测DESIGNGlobal甲基化:1)通过EpigenDx富集LINE-1重复序列,2)通过Epigentek对基因组5-甲基胞嘧啶敏感的elisa免疫分析法。在选定的候选肥胖基因位点上使用甲基化特异性PCR确定靶基因甲基化模式。研究参与者被招募为正在进行的肥胖相关基因组学和普瑞德-威利综合征研究项目的一部分。参与者:非综合征性肥胖(N=26)、消瘦(N=26)和PWS (N=39)患者。结果对PWS 15q11-q13基因组关键区域内选择的靶基因的印迹状态进行了详细的表征,结果显示印迹基因的顺式甲基化增强,而反式甲基化没有增强。在非综合征性肥胖、PWS和非肥胖对照组中,总体甲基化未发现显著差异。干预措施主要结局指标甲基化百分比和甲基化指数。结论基因组印迹效应在PWS中上游和下游15q11-q13区域的错误导致甲基化异常,印迹基因的顺式甲基化增强而非反式甲基化。使用所描述的方法,我们的受试者队列中的肥胖似乎没有影响全球甲基化水平。
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Examination of Global Methylation and Targeted Imprinted Genes in Prader-Willi Syndrome.
CONTEXT Methylation changes observed in Prader-Willi syndrome (PWS) may impact global methylation as well as regional methylation status of imprinted genes on chromosome 15 (in cis) or other imprinted obesity-related genes on other chromosomes (in trans) leading to differential effects on gene expression impacting obesity phenotype unique to (PWS). OBJECTIVE Characterize the global methylation profiles and methylation status for select imprinted genes associated with obesity phenotype in a well-characterized imprinted, obesity-related syndrome (PWS) relative to a cohort of obese and non-obese individuals. DESIGN Global methylation was assayed using two methodologies: 1) enriched LINE-1 repeat sequences by EpigenDx and 2) ELISA-based immunoassay method sensitive to genomic 5-methylcytosine by Epigentek. Target gene methylation patterns at selected candidate obesity gene loci were determined using methylation-specific PCR. SETTING Study participants were recruited as part of an ongoing research program on obesity-related genomics and Prader-Willi syndrome. PARTICIPANTS Individuals with non-syndromic obesity (N=26), leanness (N=26) and PWS (N=39). RESULTS A detailed characterization of the imprinting status of select target genes within the critical PWS 15q11-q13 genomic region showed enhanced cis but not trans methylation of imprinted genes. No significant differences in global methylation were found between non-syndromic obese, PWS or non-obese controls. INTERVENTION None. MAIN OUTCOME MEASURES Percentage methylation and the methylation index. CONCLUSION The methylation abnormality in PWS due to errors of genomic imprinting effects both upstream and downstream effectors in the 15q11-q13 region showing enhanced cis but not trans methylation of imprinted genes. Obesity in our subject cohorts did not appear to impact global methylation levels using the described methodology.
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