Tourancheau A, Rouleau M, Guauque-Olarte S, Villeneuve L, Gilbert I, Droit A, Guillemette C
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire (CHU) de Québec Research Center (CRCHU), Québec, QC, Canada.
Faculty of Pharmacy, Laval University, Québec, QC, Canada.
Pharmacogenomics J. 2018 Apr;18(2):251-261. doi: 10.1038/tpj.2017.5. Epub 2017 Apr 25.
Alternative splicing as a mean to control gene expression and diversify function is suspected to considerably influence drug response and clearance. We report the quantitative expression profiles of the human UGT genes including alternatively spliced variants not previously annotated established by deep RNA-sequencing in tissues of pharmacological importance. We reveal a comprehensive quantification of the alternative UGT transcriptome that differ across tissues and among individuals. Alternative transcripts that comprise novel in-frame sequences associated or not with truncations of the 5'- and/or 3'- termini, significantly contribute to the total expression levels of each UGT1 and UGT2 gene averaging 21% in normal tissues, with expression of UGT2 variants surpassing those of UGT1. Quantitative data expose preferential tissue expression patterns and remodeling in favor of alternative variants upon tumorigenesis. These complex alternative splicing programs have the strong potential to contribute to interindividual variability in drug metabolism in addition to diversify the UGT proteome.
可变剪接作为一种控制基因表达和使功能多样化的方式，被怀疑会对药物反应和清除产生重大影响。我们报告了人类UGT基因的定量表达谱，包括通过深度RNA测序在具有药理学重要性的组织中建立的先前未注释的可变剪接变体。我们揭示了不同组织和个体间可变UGT转录组的全面定量情况。包含与5'和/或3'末端截断相关或不相关的新读框序列的可变转录本，对每个UGT1和UGT2基因的总表达水平有显著贡献，在正常组织中平均为21%，其中UGT2变体的表达超过UGT1。定量数据揭示了肿瘤发生时优先的组织表达模式以及向可变变体的重塑。这些复杂的可变剪接程序除了使UGT蛋白质组多样化外，还有很强的潜力导致个体间药物代谢的差异。
