AID stabilizes stem cell phenotype by removing epigenetic memory of pluripotency genes

The activation-induced cytidine deaminase enzyme (AID) is required for somatic hyper-mutation and class switch recombination at the immunoglobulin locus(1). In GC-B cells, AID is highly expressed, with inherent mutator activity that helps generate antibody diversity(2). However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine (5mC) in concert with base excision repair to exchange cytosine(3). This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells(4). However, different studies have suggested either a requirement(5) or a lack of function(6) for AID promoting pluripotency in somatic nuclei following fusion with embryonic stem cells (ESCs). We tested directly whether AID regulates epigenetic memory, by comparing the relative ability of cells lacking AID to reprogram from a differentiated cell type to an induced pluripotent stem cell (iPSC). We show that AID-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize the pluripotent state. The genome of AID-null cells remains hyper-methylated in reprogramming cells, and hyper-methylated genes associated with pluripotency fail to be stably up-regulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status(7), and implicated a secondary set of pluripotency network components(8). AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state.