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

The Pharmacogenomics Journal volume 16, pages 60–70 (2016)Cite this article

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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 10 human UGT gene loci 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.

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Acknowledgements

We thank the Genomics Analysis Platform of the Institut de Biologie Integrative et des Systèmes (IBIS; Laval University, Québec, Canada) for their help in RNA-Seq experiments. We also acknowledge the excellent artwork by France Couture. This work was supported by the Canadian Institutes of Health Research (CIHR) [MOP-42392, to CG]; and the Canada Research Chair in Pharmacogenomics (Tier I) to CG. GM was supported by a graduate scholarship from the Fonds d’enseignement et de recherché (FER), Laval University. EL is a recipient of a Health Research clinician-scientist phase II CIHR award and Prostate Cancer Canada rising star award [RS2013-55].

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Authors and Affiliations

  1. Pharmacogenomics Laboratory, Centre Hospitalier Universitaire (CHU) de Québec Research Center, Québec, QC, Canada

    A Tourancheau, G Margaillan, M Rouleau, I Gilbert, L Villeneuve, E Lévesque & C Guillemette

  2. Faculty of Pharmacy, Laval University, Québec, QC, Canada

    A Tourancheau, G Margaillan, M Rouleau, I Gilbert, L Villeneuve & C Guillemette

  3. Faculty of Medicine, Laval University, Québec, QC, Canada

    E Lévesque & A Droit

  4. Canada Research Chair in Pharmacogenomics, Pharmacogenomics Laboratory, CHU de Quebec Research Center, Quebec, QC, Canada

    C Guillemette

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  1. A Tourancheau
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Correspondence to C Guillemette.

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Tourancheau, A., Margaillan, G., Rouleau, M. et al. Unravelling the transcriptomic landscape of the major phase II UDP-glucuronosyltransferase drug metabolizing pathway using targeted RNA sequencing. Pharmacogenomics J 16, 60–70 (2016). https://doi.org/10.1038/tpj.2015.20

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