Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon (A.J.A., C.B.M., P.L.I.) and United States Army Research Institute for Infectious Disease, Frederick, Maryland (P.L.I.)
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon (A.J.A., C.B.M., P.L.I.) and United States Army Research Institute for Infectious Disease, Frederick, Maryland (P.L.I.).
Drug Metab Dispos. 2020 Apr;48(4):272-287. doi: 10.1124/dmd.119.089102. Epub 2020 Jan 24.
The human genome encodes 48 nuclear receptor (NR) genes, whose translated products transform chemical signals from endo-xenobiotics into pleotropic RNA transcriptional profiles that refine drug metabolism. This review describes the remarkable diversification of the 48 human NR genes, which are potentially processed into over 1000 distinct mRNA transcripts by alternative splicing (AS). The average human NR expresses ∼21 transcripts per gene and is associated with ∼7000 single nucleotide polymorphisms (SNPs). However, the rate of SNP accumulation does not appear to drive the AS process, highlighting the resilience of NR genes to mutation. Here we summarize the altered tissue distribution/function of well characterized NR splice variants associated with human disease. We also describe a cassette exon visualization pictograph methodology for illustrating the location of modular, cassette exons in genes, which can be skipped in-frame, to facilitate the study of their functional relevance to both drug metabolism and NR evolution. We find cassette exons associated with all of the functional domains of NR genes including the DNA and ligand binding domains. The matrix of inclusion or exclusion for functional domain-encoding cassette exons is extensive and capable of significant alterations in cellular phenotypes that modulate endo-xenobiotic metabolism. Exon inclusion options are differentially distributed across NR subfamilies, suggesting group-specific conservation of resilient functionalities. A deeper understanding of this transcriptional plasticity expands our understanding of how chemical signals are refined and mediated by NR genes. This expanded view of the NR transcriptome informs new models of chemical toxicity, disease diagnostics, and precision-based approaches to personalized medicine. SIGNIFICANCE STATEMENT: This review explores the impact of alternative splicing (AS) on the human nuclear receptor (NR) superfamily and highlights the dramatic expansion of more than 1000 potential transcript variants from 48 individual genes. Xenobiotics are increasingly recognized for their ability to perturb gene splicing events, and here we explore the differential sensitivity of NR genes to AS and chemical exposure. Using the cassette exon visualization pictograph methodology, we have documented the conservation of splice-sensitive, modular, cassette exon domains among the 48 human NR genes, and we discuss how their differential expression profiles may augment cellular resilience to oxidative stress and fine-tune adaptive, metabolic responses to endo-xenobiotic exposure.
人类基因组编码 48 个核受体 (NR) 基因，其翻译产物将内源性和外源性化学信号转化为多效性 RNA 转录谱，从而改善药物代谢。本文描述了 48 个人类 NR 基因的显著多样化，这些基因通过选择性剪接 (AS) 可被加工成超过 1000 种不同的 mRNA 转录本。人类 NR 的平均表达量为每个基因约 21 个转录本，并与约 7000 个单核苷酸多态性 (SNP) 相关。然而，SNP 积累的速度似乎并没有驱动 AS 过程，这突显了 NR 基因对突变的抵抗力。在这里，我们总结了与人类疾病相关的经过充分表征的 NR 剪接变体的组织分布/功能变化。我们还描述了一种盒式外显子可视化图谱方法，用于说明模块化盒式外显子在基因中的位置，这些外显子可以在框架内跳过，从而促进对其与药物代谢和 NR 进化的功能相关性的研究。我们发现与 NR 基因的所有功能域（包括 DNA 和配体结合域）相关的盒式外显子。包含或排除功能域编码盒式外显子的矩阵非常广泛，能够显著改变调节内源性和外源性生物代谢的细胞表型。外显子包含选项在 NR 亚家族中分布不均，表明特定于组的弹性功能的保守性。对这种转录可塑性的更深入了解扩展了我们对化学信号如何被 NR 基因细化和介导的理解。这种对 NR 转录组的扩展视图为我们提供了新的化学毒性模型、疾病诊断以及基于精准医疗的个性化医疗方法。意义：本文探讨了选择性剪接 (AS) 对人类核受体 (NR) 超家族的影响，并强调了从 48 个单独基因中扩展出超过 1000 个潜在转录变体。越来越多的人认识到外源性化学物质有能力干扰基因剪接事件，在这里，我们探讨了 NR 基因对 AS 和化学暴露的敏感性差异。使用盒式外显子可视化图谱方法，我们记录了 48 个人类 NR 基因中剪接敏感的模块化盒式外显子结构域的保守性，并讨论了它们的差异表达谱如何增强细胞对氧化应激的抵抗力，并微调对内源性和外源性生物代谢物暴露的适应性、代谢反应。
