Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain

Igor Bazov*, Daniil Sarkisyan, Olga Kononenko, Hiroyuki Watanabe, Mumtaz Malik Taqi, Lada Stålhandske, Dineke S Verbeek, Jan Mulder, Grazyna Rajkowska, Donna Sheedy, Jillian Kril, Xueguang Sun, Ann-Christine Syvänen, Tatiana Yakovleva, Georgy Bakalkin

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

4 Citaten (Scopus)

Samenvatting

Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (d1PFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in d1PFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in d1PFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.

Originele taal-2English
Pagina's (van-tot)3129-3142
Aantal pagina's14
TijdschriftCerebral Cortex
Volume28
Nummer van het tijdschrift9
Vroegere onlinedatum28-jul-2017
DOI's
StatusPublished - sep-2018

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