Mouse models of colitis have been used to study the pathogenesis of inflammatory bowel disease (IBD) and for pre-clinical development of therapeutic agents. Various epigenetic pathways have been shown to play important regulatory roles in IBD. Reversible N-methyladenosine (mA) methylation represents a new layer of post-transcriptional gene regulation that affects a variety of biological processes. We aim to study how deletion of a critical component of mA writer complex, METTL14, in T cells affects the development of colitis.
Conditional Mettl14 was lineage specifically deleted with CD4-regulated Cre in T cells. Colitis phenotype was determined by H&E staining, colon weight/length ratio and cytokine expression. We additionally utilized T cell transfer model of colitis and adoptive transfer of regulatory T cells. Mice were treated with antibiotics to determine if the colitis could be attenuated.
METTL14 deficiency in T cells induced spontaneous colitis in mice. This was characterized by increased inflammatory cell infiltration, increased colonic weight/length ratio and increased Th1 and Th17 cytokines. The colitis development was due to dysfunctional regulatory T (T) cells, as adoptive transfer of wild-type T cells attenuated the colitis phenotype. The METTL14 deficient T cells have decreased RORγt expression compared to wild-type controls. METTL14 deficiency caused impaired induction of naïve T cells into induced T cells. Antibiotic treatment notably attenuated the colitis development.
Here we report a new mouse model of spontaneous colitis based on perturbation of RNA methylation in T cells. The colitis is T cell-mediated and dependent on the microbiome. This model represents a new tool for elucidating pathogenic pathways, studying the contribution of intestinal microbiome and preclinical testing of therapeutic agents for inflammatory bowel disease.

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