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The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure.
Epigenetics & Chromatin ( IF 4.2 ) Pub Date : 2020-03-16 , DOI: 10.1186/s13072-020-00338-8
Dana M Freeman 1 , Dan Lou 1 , Yanqiang Li 1 , Suzanne N Martos 1 , Zhibin Wang 1, 2, 3
Affiliation  

BACKGROUND 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. RESULTS 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. CONCLUSIONS 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.

中文翻译:

人类细胞中保守的 DNMT1 依赖性甲基化区域很容易受到神经毒性鱼藤酮的影响。

背景技术等位基因特异性 DNA 甲基化 (ASM) 描述了仅在一个遗传等位基因上维持 CpG 甲基化而不是在两个等位基因之间协调甲基化的基因组位点。这些区域中最突出的是种系 ASM (gASM),它以依赖于亲本的方式控制印记基因的表达,并与疾病相关。然而,我们最近的报告揭示了非印记基因上的大量 ASM。这些非种系 ASM 依赖于 DNA 甲基转移酶 1 (DNMT1),并引人注目地显示出小鼠基因组中随机、可切换的单等位基因甲基化模式的特征。这些 ASM 对人类健康的重要性尚未得到探讨。由于它们与 gASM 具有共同的等位性,在此,我们提出非传统 ASM 对与人类疾病相关的暴露敏感。结果我们首先探索它们在人类基因组中的保守性。我们的数据表明,我们假定的非种系 ASM 位于人类基因组的保守区域,并且位于对神经元发育和成熟至关重要的基因附近。接下来,我们将人胚胎肾细胞 HEK293 与神经毒剂鱼藤酮暴露 24 小时,测试了这些区域假设的脆弱性。事实上,根据 RNA 测序结果,与我们确定的区域相邻的 14 个基因存在差异表达。我们分析了预测的非种系 ASM 在两个神经基因 HCN2 和 NEFM 上的碱基分辨率甲基化模式,这可能会增加神经退行性变的风险。这两个区域对鱼藤酮的反应均显着低甲基化。结论 我们的数据表明,非种系 ASM 在小鼠和人类基因组之间似乎是保守的,与重要的调节因子结合基序重叠,并调节对神经元功能至关重要的基因的表达。这些结果支持这样的观点,即 ASM 对鱼藤酮等环境因素敏感,并且可能通过扰乱神经元发育来改变晚年患神经系统疾病的风险。
更新日期:2020-04-22
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