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Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues
A Tourancheau1,2, M Rouleau1,2, S Guauque-Olarte
1Pharmacogenomics Laboratory, Centre Hospitalier Universitaire (CHU) de Québec Research Center (CRCHU), Québec, QC, Canada.
The Pharmacogenomics Journal
|April 26, 2017
Summary
Alternative splicing of UDP-glucuronosyltransferase (UGT) genes generates diverse transcripts, impacting drug metabolism variability. These novel variants significantly contribute to UGT expression across tissues and individuals.
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Gene Expression
Background:
- Alternative splicing regulates gene expression and protein function.
- UDP-glucuronosyltransferase (UGT) enzymes are crucial for drug metabolism.
- Interindividual variability in drug response is partly due to genetic factors.
Purpose of the Study:
- To quantify the expression profiles of human UGT genes, including previously unannotated alternatively spliced variants.
- To investigate the contribution of alternative splicing to the UGT transcriptome in different tissues and individuals.
- To explore the role of alternative splicing in drug metabolism and UGT proteome diversification.
Main Methods:
- Deep RNA-sequencing was employed to profile UGT gene expression.
- Quantitative analysis of alternatively spliced variants was performed.
- Comparative analysis of UGT expression in normal and tumor tissues was conducted.
Main Results:
- A comprehensive quantification of the alternative UGT transcriptome was established, revealing tissue-specific and interindividual differences.
- Alternatively spliced UGT transcripts, including novel sequences, constitute a significant portion (average 21%) of total UGT gene expression.
- Expression of UGT2 variants was found to surpass that of UGT1 variants, with notable shifts during tumorigenesis.
Conclusions:
- Complex alternative splicing programs in UGT genes significantly contribute to the diversity of the UGT proteome.
- These splicing variations are a key factor in interindividual variability of drug metabolism.
- Understanding the alternative UGT transcriptome is essential for predicting drug response and optimizing pharmacotherapy.
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