Regulatory T cells (Treg) are the main mediators of dominant tolerance. Their mechanisms of action and applications are subjects of considerable debate currently. However, a human micro-RNA Treg signature has not been described yet. We investigated human natural Tregs and identified a signature composed of five micro-RNAs (-21, -31, -125a, -181c, and -374) among which miR-31 and miR-125a were under-expressed. We identified a functional target sequence for miR-31 in the 3' UTR of FOXP3 mRNA and showed using lentiviral transduction of fresh cord blood T cells, that miR-31 and miR-21 had direct negative and indirect positive effects respectively on FOXP3 expression levels. Based on recently published data demonstrating the effect of HDAC inhibitors on FOXP3 expression, we investigated, in the cord blood non-Tregs, the mechanisms by which the aspecific opening of FOXP3 chromatin could lead to an increased expression. We therefore focused on both, potential binding factors to the FOXP3 promoter region rendered accessible via the use of the HDAC inhibitor, valproate, and on possible modifications of expression of the miRs differentially expressed in Tregs. Thus, we uncovered the role of some Ets binding sites located in the FOXP3 promoter and found that Ets-1, and Ets-2 positively regulated FOXP3 expression only when the promoter region was made accessible by valproate treatment. When looking at the miR profile, we found that, following valproate treatment, the non-Tregs exhibited a signature (miR-21, miR-31, and miR-125a) similar to the one of natural Tregs (nTregs). Thus, the epigenetic control of FOXP3 expression is mediated by the accessibility of Ets binding factors, after valproate treatment, to their binding sites in the promoter region allowing thereafter the non-Tregs to acquire a miR expression profile similar to nTregs. This last observation opens up the question of the utility of this compound in the treatment of diseases linked to a deficit or an excess of Tregs, but this needs further investigation.