Activation-induced cytidine deaminase promotes DNA demethylation and expression of the Ninjurin-2 gene.

Activation-induced cytidine deaminase (AID) is expressed in germinal center B cells and contributes to somatic hypermutation and isotype switching of immunoglobulins. AID is also reportedly expressed in colonic epithelial cells (CECs) during inflammation. However, the physiological roles of AID in CECs are largely unknown. Here, we identify 619 genes, the expression of which is induced in a colorectal cancer (CRC) cell line (DLD-1) by overexpression of AID. These genes include those associated with the phosphoinositide-3-kinase-protein kinase B, mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways. We focused on the NINJ2 gene, the expression of which increased more than fivefold in AID-overexpressing DLD-1 cells and decreased in colitis-induced CECs of AID-knockout mice, compared with those of wild-type mice. We demonstrate that AID binds to the promoter/enhancer region of NINJ2 and induces DNA demethylation, which is often accompanied by transcriptional upregulation. Additionally, the recovery from induced colitis was significantly delayed in AID-knockout mice. These findings collectively suggest that inflammation-increased AID upregulation in CECs enhances NINJ2 transcription through DNA demethylation, potentially facilitating wound healing during recovery.