Extensive splicing of transcripts encoding the bile acid-conjugating enzyme UGT2B4 modulates glucuronidation
Bibliographic record
Abstract
BACKGROUND AND AIMS: UGT2B4 is a member of the UDP-glucuronosyltransferase (UGT) superfamily, a major detoxifying system in humans. UGT2B4 is involved in bile acids metabolism and highly expressed in liver and extrahepatic tissues. The aim of this study was to uncover new molecular mechanisms underlying interindividual variability in the UGT2B4 pathway. METHODS: We carried out a comprehensive scan for additional exons at this locus and discovered multiple alternative splicing events. We then assessed the expression profile of alternatively spliced transcripts in human tissues and the activity of the corresponding overexpressed proteins toward bile acids. RESULTS: We discovered three previously unidentified UGT2B4 exons, increasing the total known gene length to 46 kb. Molecular analyses revealed at least eight distinct mRNAs produced by (i) alternative promoter usage, (ii) complete and partial exon skipping, and (iii) use of alternative 3' splice sites. These splice variants were predominantly expressed in liver, gastrointestinal tract, and other extrahepatic tissues. Quantitative analyses of splicing events further sustain their prevalence in the liver. UGT2B4 proteins produced from these mRNA variants had undetectable transferase activity in human cells. However, when stably co-expressed with the active UGT2B4 isoform 1, three newly identified UGT2B4 isoforms (i2, i3, and i5) were found to negatively regulate glucuronidation. CONCLUSION: In addition to heritable genetic mutations and control of gene expression, the newly discovered diversity of UGT2B4 mRNAs may introduce variability in this glucuronidation pathway.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".