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首页> 外文期刊>Cell discovery. >Two approaches reveal a new paradigm of ‘switchable or genetics-influenced allele-specific DNA methylation’ with potential in human disease
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Two approaches reveal a new paradigm of ‘switchable or genetics-influenced allele-specific DNA methylation’ with potential in human disease

机译：两种方法揭示了“可转换的或遗传学影响的等位基因特异性DNA甲基化”的新范式，具有人类疾病的潜力

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Imprinted genes are vulnerable to environmental influences during early embryonic development, thereby contributing to the onset of disease in adulthood. Monoallelic methylation at several germline imprints has been reported as DNMT1-dependent. However, which of these two epigenetic attributes, DNMT1-dependence or allelic methylation, renders imprinted genes susceptible to environmental stressors has not been determined. Herein, we developed a new approach, referred to as NORED, to identify 2468 DNMT1-dependent DNA methylation patterns in the mouse genome. We further developed an algorithm based on a genetic variation-independent approach (referred to as MethylMosaic) to detect 2487 regions with bimodal methylation patterns. Two approaches identified 207 regions, including known imprinted germline allele-specific methylation patterns (ASMs), that were both NORED and MethylMosaic regions. Examination of methylation in four independent mouse embryonic stem cell lines shows that two regions identified by both NORED and MethylMosaic ( Hcn2 and Park7 ) did not display parent-of-origin-dependent allelic methylation. In these four F1 hybrid cell lines, genetic variation in Cast allele at Hcn2 locus introduces a transcription factor binding site for MTF-1 that may predispose Cast allelic hypomethylation in a reciprocal cross with either C57 or 129 strains. In contrast, each allele of Hcn2 ASM in J1 inbred cell line and Park7 ASM in four F1 hybrid cell lines seems to exhibit similar propensity to be either hypo- or hypermethylated, suggesting a ‘random, switchable’ ASM. Together with published results, our data on ASMs prompted us to propose a hypothesis of regional ‘autosomal chromosome inactivation (ACI)’ that may control a subset of autosomal genes. Therefore, our results open a new avenue to understand monoallelic methylation and provide a rich resource of candidate genes to examine in environmental and nutritional exposure models.
机译：印迹的基因在早期胚胎发育过程中容易受到环境的影响，从而导致成年期疾病的发作。据报道，在几个种系印迹上的单等位甲基化为DNMT1依赖性。但是，尚未确定这两种表观遗传属性，DNMT1依赖性或等位基因甲基化中的哪一种使印迹基因易受环境胁迫。在这里，我们开发了一种新的方法，称为NORED，以在小鼠基因组中鉴定2468依赖DNMT1的DNA甲基化模式。我们进一步开发了一种基于不依赖遗传变异的方法（称为甲基马赛克）的算法，以检测具有双峰甲基化模式的2487个区域。两种方法确定了207个区域，包括已知的印迹种系等位基因特异性甲基化模式（ASM），它们都是NORED和MethylMosaic区域。四个独立的小鼠胚胎干细胞系中的甲基化检查表明，由NORED和MethylMosaic识别的两个区域（Hcn2和Park7）没有显示出起源于母体的等位基因甲基化。在这四个F1杂种细胞系中，Hcn2基因座的Cast等位基因的遗传变异为MTF-1引入了一个转录因子结合位点，该位点可能使Cast等位基因的低甲基化与C57或129菌株成对。相比之下，J1近交细胞系中Hcn2 ASM的每个等位基因和四个F1杂种细胞系中的Park7 ASM的等位基因似乎都表现出相似的低甲基化或高甲基化趋势，表明“随机，可转换” ASM。连同已发表的结果，我们关于ASM的数据促使我们提出了可能控制常染色体基因子集的区域“常染色体失活（ACI）”的假设。因此，我们的研究结果为了解单等位基因甲基化开辟了一条新途径，并为在环境和营养暴露模型中进行检查的候选基因提供了丰富的资源。

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