PUBLICATION
TNF Promoter Hypomethylation Is Associated With Mucosal Inflammation in IBD and Anti-TNF Response
- Authors
- Levic, D.S., Niedzwiecki, D., Kandakatla, A., Karlovich, N.S., Juneja, A., Park, J., Stolarchuk, C., Adams, S., Willer, J.R., Schaner, M.R., Lian, G., Beasley, C., Marjoram, L., Flynn, A.D., Valentine, J.F., Onken, J.E., Sheikh, S.Z., Davis, E.E., Evason, K.J., Garman, K.S., Bagnat, M.
- ID
- ZDB-PUB-240918-12
- Date
- 2024
- Source
- Gastro hep advances 3: 888898888-898 (Journal)
- Registered Authors
- Bagnat, Michel, Davis, Erica, Evason, Kimberley, Willer, Jason
- Keywords
- Anit-TNF Response, Epigenetics, Inflammatory Bowel Disease, Methylation
- MeSH Terms
- none
- PubMed
- 39286616 Full text @ Gastro Hep Adv
Citation
Levic, D.S., Niedzwiecki, D., Kandakatla, A., Karlovich, N.S., Juneja, A., Park, J., Stolarchuk, C., Adams, S., Willer, J.R., Schaner, M.R., Lian, G., Beasley, C., Marjoram, L., Flynn, A.D., Valentine, J.F., Onken, J.E., Sheikh, S.Z., Davis, E.E., Evason, K.J., Garman, K.S., Bagnat, M. (2024) TNF Promoter Hypomethylation Is Associated With Mucosal Inflammation in IBD and Anti-TNF Response. Gastro hep advances. 3:888898888-898.
Abstract
Background and aims Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the tumor necrosis factor (TNF) promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and nonresponders.
Methods We obtained mucosal biopsies from 200 participants (133 IBDs and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 nonresponders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency.
Results TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated intestinal epithelial cells from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF nonresponders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed 2 missense variants in DNA methyltransferase 1, 1 of which had reduced function in vivo.
Conclusion Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping