Figure 6.

Model for integration of epigenetic and transcriptional mechanisms of cell type-specific PDYN expression in the human dlPFC. USF2, the ubiquitous TF expressed at high levels in subpopulation of neurons, activates PDYN transcription through binding to nonmethylated E-box in the short, nucleosome size human promoter-specific CGI in PDYN, which is hypomethylated in neurons. This results in co-localization of USF2 and PDYN proteins. In non-neuronal cells the CGI is hypermethylated that prevents activation of PDYN transcription by USF2, which is also present in these cells albeit at low levels. Methylation levels of DMR2 are opposite to those of the DMR1/CGI both in neurons and glia. This reciprocal pattern may contribute to differential PDYN transcription in neurons and non-neuronal cells; DMR2 may be targeted by a methylation-dependent transcriptional activator in neurons and/or methylation-sensitive transcriptional repressor in non-neuronal cells. Segregation of activating and restricting mechanisms could ensure contrasting PDYN expression in neurons and glia.