PCB126 Exposure Revealed Alterations in m6A RNA Modifications in Transcripts Associated With AHR Activation
PCB126 Exposure Revealed Alterations in m6A RNA Modifications in Transcripts Associated With AHR Activation
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DOI：
10.1093/toxsci/kfaa158
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发表时间：
2021-01-01
影响因子：
3.8
通讯作者：
Karchner, Sibel, I
中科院分区：
文献类型：
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作者：
Aluru, Neelakanteswar;Karchner, Sibel, I
蛋白质、DNA和RNA部分的化学修饰在调节基因表达方面起着关键作用。新的证据表明，RNA修饰(表位转录组学)在基本的生物学过程中具有实质性的作用。MRNA和非编码RNA中最常见的修饰之一是N-6-甲基腺苷(M6A)。在mRNAs的一个子集中，m6A位点优先富含在终止密码子附近、30个UTRs和外显子内，这表明m6A在mRNA的加工和功能调节中发挥着重要作用，包括选择性剪接和基因表达。关于环境化学物质暴露对m6A修饰的影响，人们知之甚少。由于许多常见的环境污染物会改变基因表达谱，并对生理过程产生不利影响，因此了解暴露对这一重要的基因调控层的影响是很重要的。因此，这项研究的目的是描述发育过程中暴露于PCB126的急性影响，PCB126是一种与环境相关的二恶英样多氯联苯，对m6A甲基化模式的影响。我们从受精后72小时开始将斑马鱼胚胎暴露在PCB126中6小时，并使用甲基化RNA免疫沉淀和测序(MERIP-SEQ)对m6A RNA进行了分析。我们的分析显示，DMSO和PCB126样品中分别有117和217个m6A峰(错误发现率为5%)。大多数峰优先位于30个非编码子和终止密码子附近。统计分析显示，15个m6A标记的转录本因接触PCB126而出现差异甲基化。这些转录本包括已知的由AHR激动剂(如ahrra、tiparp、nfe2l2b)激活的转录本，以及其他对正常发育重要的转录本(VGF、cebpd、svd1)。这些结果表明，环境化学物质，如二恶英类多氯联苯，可能通过改变m6A水平来影响发育基因表达模式。有必要进行进一步的研究，以了解暴露相关的m6A水平变化的功能后果。
Chemical modifications of proteins, DNA, and RNA moieties play critical roles in regulating gene expression. Emerging evidence suggests the RNA modifications (epitranscriptomics) have substantive roles in basic biological processes. One of the most common modifications in mRNA and noncoding RNAs is N-6-methyladenosine (m6A). In a subset of mRNAs, m6A sites are preferentially enriched near stop codons, in 30 UTRs, and within exons, suggesting an important role in the regulation of mRNA processing and function including alternative splicing and gene expression. Very little is known about the effect of environmental chemical exposure on m6A modifications. As many of the commonly occurring environmental contaminants alter gene expression profiles and have detrimental effects on physiological processes, it is important to understand the effects of exposure on this important layer of gene regulation. Hence, the objective of this study was to characterize the acute effects of developmental exposure to PCB126, an environmentally relevant dioxin-like PCB, on m6A methylation patterns. We exposed zebrafish embryos to PCB126 for 6h starting from 72h post fertilization and profiled m6A RNA using methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq). Our analysis revealed 117 and 217 m6A peaks in the DMSO and PCB126 samples (false discovery rate 5%), respectively. The majority of the peaks were preferentially located around the 30 UTR and stop codons. Statistical analysis revealed 15 m6A marked transcripts to be differentially methylated by PCB126 exposure. These include transcripts that are known to be activated by AHR agonists (eg, ahrra, tiparp, nfe2l2b) as well as others that are important for normal development (vgf, cebpd, sned1). These results suggest that environmental chemicals such as dioxin-like PCBs could affect developmental gene expression patterns by altering m6A levels. Further studies are necessary to understand the functional consequences of exposure-associated alterations in m6A levels.