The contribution of active and passive mechanisms of 5mC and 5hmC removal in human T lymphocytes is differentiation- and activation-dependent

In mammals, the 5'-methylcytosine (5mC) modification in the genomic DNA contributes to the dynamic control of gene expression. 5mC erasure is required for the activation of developmental programs and occurs either by passive dilution through DNA replication, or by enzymatic oxidation of the methyl mark to 5-hydroxymethylcytosine (5hmC), which can persist as such or undergo further oxidation and enzymatic removal. The relative contribution of each mechanism to epigenetic control in dynamic biological systems still remains a compelling question. To explore this critical issue, we used primary human T lymphocytes, in which two cellular states can be clearly identified, namely quiescent naive T cells, which are slowly or rarely proliferating, and rapidly proliferating activated T cells. We found that active mechanisms of methylation removal were selectively at work in naive T cells, while memory T lymphocytes entirely relied on passive, replication-dependent dilution, suggesting that proliferative capacity influences the choice of the preferential demethylation mechanism. Active processes of demethylation appear to be critical in quiescent naive T lymphocytes for the maintenance of regulatory regions poised for rapid responses to physiological stimuli.