The Perichromatin Region (PR) is the 200-nm-thick rim surrounding the condensed chromatin areas in the interphase cell nucleus. First described by Bernhard (1969), PR has been studied for years and several fundamental processes have been shown to take place there: DNA replication, repair, transcription, co-transcriptional splicing. Recently we have pointed out that possibly other mechanisms occur in that region (Masiello et al. 2018). We have studied the PR in several cell and tissue models, both in physiological conditions and after drug treatment. We can confirm that not only methylation on cytosine in DNA and RNA occurs there (Masiello and Biggiogera, 2017) but also demethylation of 5mC leading to 5hmC formation. We have detected by EM immunocytochemistry the presence of DNMT3 as well as TET enzymes within this area. Our data strengthens the hypothesis that PR represents one of the most active nuclear areas, where the active focus is mobile. Since only particular conditions allow its study, it will be challenging to work on PR in vivo via super resolution. References: Bernhard W (1969) A new staining procedure for electron microscopical cytology. J Ultrastruct Res 27(3):250–265 Masiello I, Biggiogera M (2017) Ultrastructural localization of 5-methylcytosine on DNA and RNA. Cell Mol Life Sci 74:3057–3064 Masiello I, Siciliani S, Biggiogera MHistochem Cell Biol (2018) 150:227–233