5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes

The main insight from this study is that the role of 5-hydroxymethylcytosine (5hmC) in postmitotic neurons is to sculpt the genome occupancy of the very abundant 5-methylcyctosine binding protein 2 (MeCP2). Accumulation of 5hmCG in transcribed genes replaces high-affinity 5mCG binding sites with low-affinity sites, decreasing MeCP2 occupancy over the transcription unit and removing its repressive effect. We refer to this role for 5hmCG as "functional demethylation" because its biochemical effect with respect to MeCP2 is equivalent to chemical demethylation: Loss of high-affinity sites for interaction in the genome. This concept reinforces the roles of 5hmC in demethylation in dividing cells by a mechanism that achieves the same goal without requiring cell division or DNA damage.