title: Transcriptional diversity at the UGT2B7 locus is dictated by extensive pre-mRNA splicing mechanisms that give rise to multiple mRNA splice variants.
abstract: OBJECTIVE
  UGT2B7 is a key member of the UDP-glucuronosyltransferase (UGT) family that participates in glucuronidation of endogenous compounds and pharmaceuticals. Much evidence suggests a large interindividual variability of UGT2B7-mediated glucuronidation, which is still unexplained by polymorphisms. We hypothesized that alternative splicing may be responsible for the variability in the UGT2B7 function.
  
  
  METHODS
  We carried out a comprehensive scan for additional exons at this locus and discovered multiple alternative splicing events. We then determined transcript expression profiles across a large variety of human tissues and assessed some of these variants for their glucuronidation activity in human cells.
  
  
  RESULTS
  In-depth analysis of the UGT2B7 gene structure led to the discovery of six novel exons. Kidney and liver samples presented the greatest enrichment of tissue-specific splicing, with 21 new UGT2B7 transcripts isolated. Furthermore, transcription from the proximal promoter (exon 1), associated with the active UGT2B7 mRNA isoform 1 (UGT2B7_v1), is most commonly observed in the gastrointestinal tract, whereas a distal promoter (exon 1a) induces the exclusion of the canonical exon 1 and is active in hormone-related tissues. We also showed that novel transcripts with alternative 3' ends could be translated into proteins lacking glucuronosyltransferase activity in human cells but acting as negative regulators on transferase activity when coexpressed with the active UGT2B7 protein.
  
  
  CONCLUSIONS
  Our findings point toward a significant variability in structure, abundance, and tissue-specific UGT2B7 transcriptome, in addition to novel functions for UGT2B7-derived proteins, all of which may ensure the production of tissue-specific proteomes and functions.
authors: Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
authors: Vincent
authors: V
authors: Ménard
authors: Olivier
authors: O
authors: Eap
authors: Joannie
authors: J
authors: Roberge
authors: Mario
authors: M
authors: Harvey
authors: Eric
authors: E
authors: Lévesque
authors: Chantal
authors: C
authors: Guillemette
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic; D012322:RNA Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D014018:Tissue Distribution / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D007527:Isoenzymes; D012322:RNA Precursors; D012333:RNA, Messenger; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase