Colonic stem cell from severe ulcerative colitis maintains environment-independent immune activation by altering chromatin accessibility and global m 6A loss

Abstract Ulcerative colitis (UC) is a chronic inflammatory disease of colon, which is characterized by crypt architectural distortion. Alternation of colonic stem cell (CoSC) contributed to the occurrence of UC, yet the regulatory mechanisms remain unclear. To investigate the dysregulation of transcriptional and post-transcriptional regulation, we performed RNA-seq, ATAC-seq, and m 6A meRIP-seq analysis of the cultured CoSCs that isolated from UC patients. The transcriptome analysis revealed distinct expression signatures of UC patients in mild and severe stages. We observed abnormal activation of immune and extracellular matrix-related genes in patients affected by severe UC. The chromatin accessibility at the promoter regions of these genes was also specifically increased in the severe stage. In addition, we identified that a global loss of RNA m 6A modification in severe stage accompanied by higher expression of the m 6A demethylase FTO. The aberrant activation of large number immune and extracellular matrix-related genes, including IL4R, HLA-DPA1 and COL6A1, was related to both gain of chromatin accessibility and loss of m 6A in severe UC patients. Our finding revealed an environment-independent immune activation of CoSCs in UC and provided FTO as a potential therapeutic target.