|AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes.
|Year of Publication
|Kumar R, DiMenna L, Schrode N, Liu T-C, Franck P, Muñoz-Descalzo S, Hadjantonakis A-K, Zarrin AA, Chaudhuri J, Elemento O, Evans T
|2013 Aug 01
|Animals, Cell Dedifferentiation, Cellular Reprogramming, Cytidine Deaminase, Epigenesis, Genetic, Female, Fibroblasts, Gene Expression Regulation, HEK293 Cells, Humans, Male, Mice, Pluripotent Stem Cells, Transcription Factors
The activation-induced cytidine deaminase (AID; also known as AICDA) enzyme is required for somatic hypermutation and class switch recombination at the immunoglobulin locus. In germinal-centre B cells, AID is highly expressed, and has an inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine in concert with base-excision repair to exchange cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, different studies have suggested either a requirement or a lack of function for AID in promoting pluripotency in somatic nuclei after fusion with embryonic stem cells. Here we tested directly whether AID regulates epigenetic memory by comparing the relative ability of cells lacking AID to reprogram from a differentiated murine cell type to an induced pluripotent stem cell. 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 in the pluripotent state. The genome of Aid-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably upregulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status, and implicated a secondary set of pluripotency network components. AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state.
|PubMed Central ID
|R01 HD052115 / HD / NICHD NIH HHS / United States
T32 AI007621 / AI / NIAID NIH HHS / United States
R01 HL056182 / HL / NHLBI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
HL056182 / HL / NHLBI NIH HHS / United States
AI072194 / AI / NIAID NIH HHS / United States
R37 HL056182 / HL / NHLBI NIH HHS / United States