1. Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain
- Author
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Ann-Christine Syvänen, Igor Bazov, Lada Stålhandske, Jan Mulder, Grazyna Rajkowska, Hiroyuki Watanabe, Olga Kononenko, Mumtaz Malik Taqi, Xueguang Sun, Georgy Bakalkin, Donna Sheedy, Daniil Sarkisyan, Tatiana Yakovleva, Jillian J. Kril, Dineke S. Verbeek, Molecular Neuroscience and Ageing Research (MOLAR), and Movement Disorder (MD)
- Subjects
0301 basic medicine ,Adult ,Male ,cell type-specific expression ,HUMAN PRODYNORPHIN GENE ,Transcription, Genetic ,Cognitive Neuroscience ,USF2 ,Prefrontal Cortex ,Dynorphin ,Biology ,Epigenesis, Genetic ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,USF PROTEINS ,ATAXIA TYPE 23 ,Transcription (biology) ,mental disorders ,medicine ,Humans ,UPSTREAM STIMULATORY FACTORS ,Epigenetics ,Protein Precursors ,Opioid peptide ,Promoter Regions, Genetic ,Transcription factor ,human brain ,Aged ,BARRIER-ELEMENT ,Aged, 80 and over ,Neurons ,DNA methylation ,DNA-BINDING FACTOR ,neuropeptides ,METHYLATION ,Original Articles ,Enkephalins ,Middle Aged ,DROPLET DIGITAL PCR ,Dorsolateral prefrontal cortex ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Gene Expression Regulation ,SPINAL-CORD ,transcription ,Neuroscience ,DORSAL-HORN - Abstract
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 (dlPFC), 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 dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.
- Published
- 2018