Xenobiotic-responsive hepatic long non-coding RNAs

7.项目总结/摘要 许多工业化学品、环境污染物和其他异种化学物质激活转录因子 属于核受体超家族，这导致广泛的基因组，表观遗传和 转录变化破坏肝脏和其他组织中的关键生物学途径和代谢过程， 组织中研究建议集中在肝核受体CAR（组成型雄烷受体; NR 1 I3），它被结构多样的异种化学物质激活，并调节数百种 蛋白质编码基因对异生物质代谢、脂肪生成、葡萄糖 稳态和炎症，并已被牵连作为非酒精性脂肪肝疾病的调节剂 （NAFLD）发展。我们已经发现，CAR和其他异生物素反应性受体的异生物素激动剂， 受体诱导或抑制数百个核富集的长非编码RNA的转录 （lncRNA）具有表观遗传和基因调节潜力，其中许多具有人类直系同源物。这项建议 基于这些发现和肝细胞分区的最新进展，单细胞转录组学 分析和基因共表达网络分析，以阐明在完整小鼠肝脏模型中， CAR应答lncRNA对外源化学品暴露诱导的脂肪肝疾病的影响建议的研究 检验CAR响应性lncRNA的子集控制肝脏基因调控网络驱动的假设。 NAFLD和下游病理，失调过程如脂质和碳水化合物代谢， 肝细胞类型特异性和肝小叶区域依赖性肝结构和线粒体功能 方式提出的工作使用TCPOBOP（1，4-双[2-（3，5-二氯吡啶氧基）]苯），一种原型非 基因毒性化学物质和CAR特异性激动剂配体，以解决看似矛盾的发现， 持续暴露于外源化学CAR激活剂诱导喂食正常食物饮食的小鼠的NAFLD，但 抑制喂食高脂肪饮食的小鼠的NAFLD发展。这些研究将阐明CAR的作用， 它所调节的lncRNA在脂肪肝病因学和进展中的作用。获得的结果将给出关键的 深入了解外来化学物质失调CAR依赖性代谢的潜在机制 与NAFLD相关的途径，NAFLD影响25%的美国成年人，是肝硬化、肝细胞性肝硬化和肝硬化的主要原因。 癌症和肝功能衰竭这项工作将重新集中在异种化学作用的研究工作， 对基于单细胞的、空间分区的基因调控网络和非编码转录组的研究， 并将作为其他异常调节基因表达的外源化学激活受体的范例 复杂的方式。总之，关于CAR响应性lncRNA及其在异种化学反应中的作用的拟议研究- 诱导性肝病理学可能为预防、诊断或治疗化学性肝病提供新的途径 exposure.

7. Project Summary/Abstract Many industrial chemicals, environmental pollutants and other xenochemicals activate transcription factors belonging to the nuclear receptor superfamily, which leads to widespread genomic, epigenetic and transcriptional changes that disrupt key biological pathways and metabolic processes in liver and other tissues. The studies proposed focus on the liver nuclear receptor CAR (Constitutive Androstane Receptor; NR1I3), which is activated by structurally diverse xenochemicals and regulates transcription of hundreds of protein-coding genes important for processes such as xenobiotic metabolism, lipogenesis, glucose homeostasis, and inflammation, and has been implicated as a regulator of non-alcoholic fatty liver disease (NAFLD) development. We have discovered that xenobiotic agonists of CAR and other xenobiotic-responsive receptors induce or repress the transcription of several hundred nuclear-enriched long non-coding RNAs (lncRNAs) with epigenetic and gene regulatory potential, many of which have human orthologs. This proposal builds on these findings and on recent advances in liver cell zonation, single cell-based transcriptomic profiling, and gene co-expression network analysis to elucidate in an intact mouse liver model the effects of CAR-responsive lncRNAs on fatty liver disease induced by foreign chemical exposure. The studies proposed test the hypothesis that a subset of CAR-responsive lncRNAs control hepatic gene regulatory networks driving NAFLD and downstream pathologies, dysregulating processes such as lipid and carbohydrate metabolism, hepatic architecture and mitochondrial function in a liver cell type-specific and hepatic lobule zone-dependent manner. The work proposed uses TCPOBOP (1,4-bis[2-(3,5-dichloro-pyridyloxy)]benzene), a prototypic non- genotoxic chemical and CAR-specific agonist ligand, to address the seemingly paradoxical finding that persistent exposure to foreign chemical CAR activators induces NAFLD in mice fed normal chow diet, but suppresses NAFLD development in mice fed a high fat diet. These studies will elucidate the role of CAR, and the lncRNAs that it regulates, in fatty liver disease etiology and progression. Results obtained will give critical insight into the underlying mechanisms by which foreign chemicals dysregulate CAR-dependent metabolic pathways linked to NAFLD, which affects 25% of US adults and is a major cause of cirrhosis, hepatocellular cancer and liver failure. This work will refocus research efforts on xenochemical action to include mechanistic studies of single cell-based, spatially zonated gene regulatory networks and the non-coding transcriptome, and will serve as a paradigm for other foreign chemical-activated receptors that dysregulate gene expression in complex ways. Together, the proposed studies on CAR-responsive lncRNAs and their role in xenochemical- induced liver pathology may lead to new ways to prevent, diagnose or treat liver diseases induced by chemical exposure.