A91 NOVEL TRIM22 INTERACTIONS REVEAL POTENTIAL CAUSATIVE MECHANISMS IN VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEOIBD)
Bibliographic record
Abstract
The severe multi-systemic phenotype of VEOIBD is often difficult to treat with conventional therapies. Causative monogenic mutations have been identified, but the majority of VEOIBD patients present without any known defect. Our recently published whole exome sequencing (WES) of VEOIBD patients identified autosomal recessive variants in antiviral E3 ubiquitin ligase TRIM22, identifying its novel role in NOD2 signal regulation through interaction and ubiquitination of NOD2. TRIM22 patient variants caused aberrant NOD2 antiviral and pro-inflammatory signalling. TRIM22’s role in these pathways, and roles TRIM proteins play in proliferation and apoptosis, inspires confidence in its critical role in VEOIBD. However, the complete range of pathways influenced by TRIM22 remains a mystery. Our hypothesis that TRIM22 lies at a crossroad of multiple disease related pathways will be tested by uncovering binding partners and their clinical implications in VEOIBD. Candidate binding partners were identified by BioID, a method by which TRIM22 is fused with a promiscuous biotin ligase. Biotin affinity capture and mass spectrometry identified proximal biotinylated proteins. Co-immunoprecipitation (co-IP) and immunofluorescence (IF) were used to validate interactions. Candidates were tested with ubiquitination assays for modification by TRIM22. TRIM22 patient samples were investigated by immunohistochemistry (IHC). The BioID list was cross-referenced with our WES database for potential disease causing variants. Co-IP shows TRIM22 interaction with HDAC1, a key component of the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex involved in cell growth and apoptosis. Endogenous TRIM22 and HDAC1 show nuclear co-localization in CACO-2 colorectal adenocarcinoma and U-937 histiocytic lymphoma cell lines. TRIM22 patient variants show reduced HDAC1 binding in preliminary experiments. TRIM22 may affect HDAC1 ubiquitination state in preliminary assays. IHC of a colon sample from one TRIM22 variant patient exhibits ubiquitin aggregation occurring predominantly in the nucleus. TRIM22 BioID reveals 22 genes with potentially disease causing variants in our WES database. BioID revealed multiple Mi-2/NuRD complex proteins, suggesting a role for TRIM22 in chromatin remodeling and gene regulation. TRIM22 variants’ effects on HDAC1 binding, ubiquitination, and function could reveal a novel disease mechanism. Other candidates include associations with primary immune deficiency (e.g. cyclin T1 and associated CDK9), host-virus interaction sites, regulators of NOD2 signalling (e.g. PML), and genes within known IBD loci. The 22 potentially disease causing genes revealed by BioID can be verified by future studies, providing an example of causative gene discovery in VEOIBD with potential for personalized therapies. CIHRSickKids Research Training Competition, Helmsley Charitable Trust
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".