Laboratory of Environmental Epigenomes, Department of Environmental Health & Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
The State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, Hubei, China.
Epigenetics Chromatin. 2020 Mar 16;13(1):17. doi: 10.1186/s13072-020-00338-8.
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.
等位基因特异性 DNA 甲基化（ASM）描述了基因组中只有一个遗传等位基因保持 CpG 甲基化，而不是两个等位基因协调甲基化的区域。其中最突出的区域是种系 ASM（gASM），它们以亲本来源依赖的方式控制印迹基因的表达，并与疾病相关。然而，我们最近的报告揭示了许多非印迹基因的 ASM。这些非种系 ASM 依赖于 DNA 甲基转移酶 1（DNMT1），并且在小鼠基因组中表现出惊人的随机、可切换单等位基因甲基化模式的特征。这些 ASM 对人类健康的意义尚未被探索。由于它们与 gASM 具有共同的等位性，因此我们提出非传统的 ASM 对与人类疾病相关的暴露敏感。
我们首先探索了它们在人类基因组中的保守性。我们的数据表明，我们推测的非种系 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。我们接下来通过用神经毒素鱼藤酮处理人胚肾细胞 HEK293 24 小时来测试这些区域的假设易感性。事实上，我们鉴定的区域附近有 14 个基因的表达从 RNA-seq 中差异表达。我们分析了两个具有增加神经退行性变风险潜力的神经基因 HCN2 和 NEFM 的预测非种系 ASM 的碱基分辨率甲基化模式。两个区域在鱼藤酮的作用下均显著低甲基化。
我们的数据表明，非种系 ASM 似乎在小鼠和人类基因组之间保守，重叠重要的调控因子结合基序，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 对环境因素如鱼藤酮敏感，并且可能通过扰乱神经元发育来改变晚年神经疾病的风险。
