A91 NOVEL TRIM22 INTERACTIONS REVEAL POTENTIAL CAUSATIVE MECHANISMS IN VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEOIBD)
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».