Fig. 9.

Schematic representation depicting the epigenetic regulation of fear extinction. DNA methylation is associated with suppression of gene transcription. The precise molecular processes through which this occurs are complex. In brief, methylation of cytosines at CpG dinucleotides recruits methyl-DNA binding proteins, at specific sites in the genome. Proteins that bind to methylated DNA, including methyl CpG-binding protein 2(MeCP2) and methyl CpG-binding domain protein1 (MBD1), have both a methyl-DNA binding domain and a transcription-regulatory domain. The transcription-regulatory domain recruits adapter/scaffolding proteins, which in turn recruit HDACs, including HDAC2, to repress gene transcription [reviewed in (Sweatt, 2009). Following extinction related neuronal activity a number of molecular mechanisms are invoked, ultimately leading to facilitated histone acetylation and subsequent enhancement of gene transcription. These mechanisms include enhancement of HAT activity, such as PCAF (see text) and a reduction in HDAC activity by mechanisms which include nitrosylation (NO) of HDACs, including HDAC2, which facilitates dissociation of HDAC from the chromatin. Moreover, enhanced histone acetylation may also be mediated by the conversion of DNA demethylation which is mediated by the Tet family of methylsytosine dioxygenases. Emerging pharmaceutical evidence is showing that HDAC inhibitors can facilitate gene transcription by enhancing histone acetylation in the promoter region of extinction-relevant genes (see text).