Department of Biostatistics, University of Washington, Seattle, WA, United States of America.
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States of America.
PLoS One. 2020 Feb 26;15(2):e0224644. doi: 10.1371/journal.pone.0224644. eCollection 2020.
Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.
多溴联苯醚（PBDEs）曾被正式用作阻燃剂，具有化学稳定性和脂溶性，是已知会在人体内生物积累的持久性有机污染物。尽管其毒性已得到充分证实，但对于 PBDE 暴露引起的转录调控变化知之甚少。长非编码 RNA（lncRNA）越来越被认为是转录和翻译过程的关键调节因子。据推测，lncRNA 可以调节附近的蛋白质编码基因（PCG），lncRNA 转录的变化可能在顺式作用中扰乱其邻近 PCG 的基因表达。本研究的目的是：1）描述 PBDE 暴露后差异调控的 PCG 和 lncRNA；2）通过基因组注释和预测结合工具鉴定 PCG-lncRNA 对；3）确定差异表达 lncRNA-PCG 对引起的富集经典途径。HepaRG 细胞是源自人类的肝细胞，可准确代表人类肝组织的基因表达谱，这些细胞以 25μM 的剂量暴露于 BDE-47 和 BDE-99 中 24 小时。通过 DESeq2 和 HOMER 鉴定差异表达的 lncRNA-PCG 对；通过 IPA 确定显著的经典途径。LncTar 用于预测 19 对具有已知药物处理途径作用的 lncRNA-PCG 对的结合。基因组注释显示，大多数差异表达的 lncRNA 映射到 PCG 内含子。PBDEs 调节与 PXR 和 CAR 重叠的途径，如蛋白质泛素化途径和过氧化物酶体增殖物激活受体α-视黄酸 X 受体α（PPARα-RXRα）激活，但也调节独特的途径，涉及中间代谢。PBDEs 独特地下调 GDP-L-岩藻糖生物合成，表明其在修饰涉及碳水化合物和脂质代谢等中间代谢的重要途径中的作用。总之，我们提供了强有力的证据表明，PBDEs 以 PXR/CAR 配体依赖和独立的方式调节 PCG 和 lncRNA。
