Divergent expression and metabolic functions of human glucuronosyltransferases through alternative splicing

Purpose: Maintenance of cellular homeostasis and xenobiotics detoxification relies on the glucuronidation pathway mediated by 19 human UDP-glucuronosyltransferase enzymes (UGTs) encoded by 10 highly homologous genes. Recent evidence suggests that alternative splicing largely expands the human UGT transcriptome. Results: we establish the quantitative portrait of the UGT transcriptome in major metabolic organs and characterize cellular functions of selected alternative UGT isoforms with novel in-frame sequences. Targeted RNA sequencing uncovered that AS significantly shapes the UGT transcriptome, with variants quantitatively representing up to 35% and 60% UGT transcripts in normal and tumoral tissues respectively. Novel distinctive in-frame sequences were present in 20% alternative transcripts, which potentially encode UGT isoforms with distinct structural and functional features. Conclusions: This work exposes the important quantitative and biological significance of alternative UGT expression likely creating unparalleled protein diversity evolving from enzymes to regulators of cell metabolism. Overall design: normal and tumoral metabolic tissues by targeted RNA next-generation sequencing; Total RNA was extracted from liver, kidney, intestine and colon from multiple human donors. RNA-sequencing was conducted with a Illumina HiSeq 2500 system