Structure and Function. A. Despite being on opposite strands, CpG methylation is present in a cis relationship within the major groove of DNA. Methyl groups on the CpG site shown in yellow. B. DNA methylation can blocks transcription factor binding. Hemi-methylation recruits UHRF1 that localizes DNMT1 and HDACs. CpG methylation recruits MBD proteins that bind HDACs and histone methyltransferases (HMTs). These processes lead to an increasing chromatin compaction and gene silencing. C. dCas9 and TALE epigenetic modifiers targeted therapies could be utilized to increase the expression of Ube3a and Tcf4 for the treatment of Angelman Syndrome and Pitt-Hopkins Syndrome, respectively. TF, transcription factor; HMT, histone methyltransferase, gRNA, guide RNA; DNMTcd, DNMT catalytic domain; TETcd, TET catalytic domain.