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首页> 外文期刊>Epigenetics & Chromatin >The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure
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The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

机译：人细胞中保守的DNMT1依赖性甲基化区域易受神经毒剂旋转酮暴露的影响

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Allele-specific DNA methylation (ASM) describes genomic loci that maintain CpG methylation at only one inherited allele rather than having coordinated methylation across both alleles. The most prominent of these regions are germline ASMs (gASMs) that control the expression of imprinted genes in a parent of origin-dependent manner and are associated with disease. However, our recent report reveals numerous ASMs at non-imprinted genes. These non-germline ASMs are dependent on DNA methyltransferase 1 (DNMT1) and strikingly show the feature of random, switchable monoallelic methylation patterns in the mouse genome. The significance of these ASMs to human health has not been explored. Due to their shared allelicity with gASMs, herein, we propose that non-traditional ASMs are sensitive to exposures in association with human disease. We first explore their conservancy in the human genome. Our data show that our putative non-germline ASMs were in conserved regions of the human genome and located adjacent to genes vital for neuronal development and maturation. We next tested the hypothesized vulnerability of these regions by exposing human embryonic kidney cell HEK293 with the neurotoxicant rotenone for 24?h. Indeed,14 genes adjacent to our identified regions were differentially expressed from RNA-sequencing. We analyzed the base-resolution methylation patterns of the predicted non-germline ASMs at two neurological genes, HCN2 and NEFM, with potential to increase the risk of neurodegeneration. Both regions were significantly hypomethylated in response to rotenone. Our data indicate that non-germline ASMs seem conserved between mouse and human genomes, overlap important regulatory factor binding motifs, and regulate the expression of genes vital to neuronal function. These results support the notion that ASMs are sensitive to environmental factors such as rotenone and may alter the risk of neurological disease later in life by disrupting neuronal development.
机译：特异性DNA甲基化（ASM）描述了在仅在两个等位基因中仅维持CpG甲基化的基因组基因座，而不是在两个等位基因中具有协调的甲基化。这些区域中最突出的是种系ASM（Gasms），其控制在原始依赖性方式的父母中并与疾病相关的印迹基因的表达。然而，我们最近的报告显示了非印记基因的许多ASM。这些非系列ASM依赖于DNA甲基转移酶1（DNMT1）并尖锐地显示小鼠基因组中随机可切换单邻甲基化模式的特征。尚未探讨这些ASM对人类健康的重要性。由于它们与胃部的共同等位基因，这里，我们提出了非传统的ASM对与人类疾病相关的暴露敏感。我们首先在人类基因组中探索他们的保护。我们的数据显示，我们推定的非系列ASM在人类基因组的保守区域中，位于神经元发育和成熟至关重要的基因附近。我们接下来通过将人胚胎肾细胞HEK293与神经毒剂旋转源暴露24μm，测试这些区域的假设脆弱性。实际上，与我们所识别的区域相邻的14个基因从RNA测序差异表达。我们分析了在两个神经基因，HCN2和Nefm下预测的非系列ASM的基本分辨率甲基化模式，其可能增加神经变性的风险。响应于旋转酮，这两个地区都显着脱甲基化。我们的数据表明，小鼠和人类基因组之间的非系列Asms似乎是保守的，重叠重要的调节因子结合基序，并调节基因的表达至神经元功能。这些结果支持了ASM对Rotenone等环境因素敏感的观点，并且可以通过破坏神经元发育来改变生命后面的神经病毒疾病的风险。

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