Unravelling the transcriptomic landscape of the major phase II UDP-glucuronosyltransferase drug metabolizing pathway using targeted RNA sequencing

Authors: Tourancheau, Alan; Margaillan, Guillaume; Rouleau, Michèle; Gilbert, Isabelle; Villeneuve, Lyne; Lévesque, Éric; Droit, ArnaudGuillemette, Chantal
Abstract: A comprehensive view of the human UDP-glucuronosyltransferase (UGT) transcriptome is a prerequisite to the establishment of an individual’s UGT metabolic glucuronidation signature. Here, we uncover the transcriptome landscape of the ten human UGT loci genes in normal and tumoral metabolic tissues by targeted RNA next generation sequencing. Alignment on the human hg19 reference genome identifies 234 novel exon-exon junctions. We recover all previously known UGT1 and UGT2 enzyme-coding transcripts and identify over 130 structurally and functionally diverse novel UGT variants. We further expose a revised genomic structure of UGT loci and provide a comprehensive repertoire of transcripts for each UGT gene. Data also uncover a remodelling of the UGT transcriptome occurring in a tissue- and tumor-specific manner. The complex alternative splicing program regulating UGT expression and protein functions is likely critical in determining detoxification capacity of an organ and stress-related responses, with significant impact on drug responses and diseases. Keywords: Alternative splicing, transcriptome, glucuronidation, RNA sequencing, drug metabolism, glucuronosyltransferase (UGT)
Issue Date: 14 April 2015
Open Access Date: 14 March 2016
Document version: VoR
Permalink: http://hdl.handle.net/20.500.11794/207
This document was published in: The pharmacogenomics journal, Vol (16), 60–70 (2015)
http://dx.doi.org/10.1038/tpj.2015.20
Nature
Alternative version: http://www.ncbi.nlm.nih.gov/pubmed/25869014
Collection:Articles publiés dans des revues avec comité de lecture

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