Fig. 8.

Model of DNA promoter cytosine methylation dynamics in vascular smooth muscle (VSM) phenotype switching. Left: in proliferative synthetic phenotype VSM cells, relatively high expression of thymine DNA glycosylase (TDG) compared with ten-eleven translocations (TETs) results in a TET rate-limited state favoring accumulation of methylated cytosine in specific genes, including Ca²⁺/calmodulin-dependent protein kinase IIγ and contractile protein genes, repressing their expression. Right: differentiation of VSM is associated with increased expression of TETs and a strong decrease in TDG expression, resulting in a TDG rate-limited state with TET-mediated demethylation and accumulation of 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC) modifications on the promoters of VSM-differentiated genes, leading to de-repression and/or activated expression. Dynamically switching back to a VSM synthetic phenotype as a consequence of vascular disease or injury requires downregulation of TET expression, cell cycling to passively restore and re-expression of TDG to actively restore, unmodified cytosine as substrates for DNA methyltransferase (DNMT) with consequent remethylation, and repressed expression of specific genes.