A244 ROLE OF THE NUCLEAR RECEPTOR HNF4α AND ITS MANY ISOFORMS IN COLORECTAL CANCER
Bibliographic record
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor regulating the expression of intestinal epithelial genes. Up to 12 HNF4α isoforms can be produced by the use of promoters P1 and P2, and alternative splicing. HNF4α has recently been associated with colorectal cancer, and the variable expression of the P1 and P2 classes could explain the contradictory roles of HNF4α in this disease. However, little is known on the specific functions for each HNF4α isoform during colorectal cancer. The overall aim of this study was to elucidate how HNF4α, through the expression of its many isoforms in the colon, may contribute to the progression of colorectal cancer. More specifically, the twelve HNF4α isoforms were functionally characterized by evaluating their DNA binding and transactivation capabilities, and identifying distinct protein interaction networks using quantitative proteomics. Expression of the HNF4α isoforms was evaluated by RT-PCR in different cell lines and in different human gastrointestinal tissues. Stable cell lines expressing each of the twelve isoforms tagged with either GFP or BioID2 proteins were generated in the HCT116 human colorectal cancer cell line. EMSA, luciferase and qPCR assays were performed to characterize every single isoform. Protein interaction networks for specific isoforms expressed in the colon were characterized by quantitative mass spectrometry. Important variations in the expression of HNF4α isoforms were first observed by RT-PCR in different colorectal cancer cell lines as well as in several healthy human gastrointestinal tissues. Stable HCT116 cell lines expressing each of the HNF4α isoforms in an inducible manner were generated. Although each isoform was expressed and localized in the nucleus with a similar pattern, EMSA assays revealed differences in DNA binding capabilities for a subset of isoforms. This correlated with differences observed in the transactivation potential of these isoforms, as determined by luciferase assays and qPCR. Finally, important variations in the protein interactomes for these different isoforms were detected by quantitative mass spectrometry. The nature of these differences was related to proteins involved in transcription and chromatin assembly regulation. Our data identified differential transcriptional properties among the various HNF4α isoforms. Specific transcriptional partners were identified to differently interact with these isoforms. It is expected that the future characterization of these specific interactions will provide insight as to why HNF4α could have both oncogenic and tumor suppressive properties during colorectal cancer. CIHRNSERC
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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) | 0.001 | 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".