A New Model of Spontaneous Colitis in Mice Induced by Deletion of an RNA m(6)A Methyltransferase Component METTL14 in T Cells

BACKGROUND AND AIMS: 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(6)-methyladenosine (m(6)A) 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 m(6)A writer complex, METTL14, in T cells affects the development of colitis. METHODS: Conditional Mettl14 was lineage specifically deleted with CD4-regulated Cre in T cells. Colitis phenotype was determined by H&E staining, colon weight-to-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. RESULTS: METTL14 deficiency in T cells induced spontaneous colitis in mice. This was characterized by increased inflammatory cell infiltration, increased colonic weight-to-length ratio and increased Th1 and Th17 cytokines. The colitis development was due to dysfunctional regulatory T (T(reg)) cells, as adoptive transfer of WT T(reg) cells attenuated the colitis phenotype. The METTL14-deficient T(reg) cells have decreased RORγt expression compared with WT controls. METTL14 deficiency caused impaired induction of naïve T cells into induced T(reg) cells. Antibiotic treatment notably attenuated the colitis development. CONCLUSION: 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.