BK Polyoma Virus Induces Aberrant Methylation of Host Genome to Promote Epithelial Mesenchymal Transition and Fibrosis
Notice bibliographique
Résumé
Although most people are infected during early childhood, BK polyoma virus (BKV) reactivates and causes disease primarily in renal transplant patients. BKV is currently the leading cause of graft loss during the first two years after renal transplant. Activation of BKV is associated with inflammation, tissue destruction and progression to fibrosis through a process involving the transformation of epithelial cells in to mesenchymal phenotype. Understanding how BKV causes these changes will help us in better prediction and management of BKV nephropathy. As the primary site of BKV tropism is renal tubular epithelial cells, it needs to device ways to promote the transition and proliferation of these terminally differentiated cells. We hypothesized that BK may activate epigenetic mechanisms to promote these changes by inducing or inhibiting key genes involved in maintaining cellular integrity and stability. DNA CpG methylation is one such epigenetic mechanism which can control gene regulation by causing changes to the DNA which inhibit the accessibility of transcription factors to gene promoters. For our experiments, we have used primary human proximal renal tubular epithelial cells (HPTC) isolated from donor kidneys or procured from ATCC. Cells were infected with BKV for different time points. Real-time expression profiling was done to identify key genes modulated by BKV. Bisulfite conversion and Methylation specific PCR was used to identify specific CpG changes induced by BKV. Sequencing of the bisulfite converted DNA was done to identify the methylation status of entire CpGs islands in the promoters of these genes. Promoter region with specific CpGs was then cloned in pGL3 luciferase reporter vector to specify the role of particular CpGs in regulation and rule out the effect of trans-acting elements. For luciferase assays, CCD1105 KIDtr and HPTC cells were transfected using Lipofectamine- LTX and Plus reagent, infected with BK virus and assayed using Dual luciferase assay. Cell cycle analysis was done using propidium iodide staining and flow cytometry. Infection of renal epithelial cells by BKV caused induction of proinflammatory genes such as Cox-2 and interleukin 1 Beta along with Vimentin which is the marker for epithelial mesenchymal transition. More importantly, it inhibited retinoblastoma (RB1) and E-cadherin (CDH1) genes. We have for the first time identified that BK inhibits these genes by causing hypermethylation of specific CpG islands in their upstream regulatory promoters. These genes are important regulators of cell-cell adhesion (CDH1) and cell cycle (RB1), and their inhibition may lead to loss of adhesion and cell proliferation respectively. Luciferase Reporter assay using cloned RB1 promoter confirmed the involvement of these CpG islands and showed progressive decrease in RB1 promoter activity with increasing BK infection. Our studies also suggest that BKV infection may lead to increased aneuploidy in these cells further contributing to cellular instability and transformation. The changes induced by BKV may ultimately lead to inflammation, cellular proliferation and progression to renal fibrosis and graft loss. Specific CpG methylation patterns induced by BKV may also serve as biomarkers to predict the initiation of BKV nephropathy and help in devising relevant control strategies.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,000 | 0,000 |
| 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 | 0,000 |
| 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 ».