Figure 1. The schematic representation of our new working model about the role of epigenetics mechanisms in the Tregs biogenesis/suppressive function and the development of autoimmune and pro-inflammatory human diseases.

Several environmental factors influence the expression of Foxp3 gene via epigenetics mechanisms. The Foxp3 transcription factor determines the suppressive function and stability of Tregs. The epigenetics changes in modulating the Foxp3 expression are mediated by different mechanisms: 1. The histone acetylation/deacetylation of Foxp3 gene by histone acetyltransferase (HTA) and histone deacetylase (HDACs) complex. The increase in histone acetylation makes the Foxp3 gene more stable in enhancing the Tregs’ supressive function. 2. The DNA methylation/demethylation of Foxp3 gene by DNA methyltranferases (DNMTs) and DNA demethylases. The demethylation of CpG islands in the genomic DNA of Foxp3 gene increases the stability of Foxp3 gene expression and leads to the stabilized suppressive capacity of Tregs. 3. The histone demethylation/methylation of Foxp3 gene mediated by histone methyltransferases (HMT) and histone demethylases. Foxp3 histone demethylation increases the development and stable Tregs phenotype. The epigenetics modification by different stimuli like hyperlipidemia, hyperhomocysteinemia, hyperglycemia, inflammation-provoking drugs and pro-inflammatory cytokines, generates an unstable Foxp3 gene, generating an imbalance among conventional T cell (Tconv.) and Treg cells, promoting the development of autoimmune and inflammatory diseases, cancers and graft-versus-host disease (GVHD). Moreover, the anti-inflammatory drugs, DNMT inhibitors and histone deacetylase inhibitors (HDIs) have the capacity of increasing the stability of Foxp3 gene, increasing the suppressive capacity of Tregs, promoting an immune tolerance environment.