Abstract
Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian clock consists of a transcriptional/translational feedback system, with several regulatory loops, that are also intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape shows profound changes in the addictive brain, with significant alterations in histone modification, DNA methylation, and small regulatory RNAs. The combination of these two observations raises the possibility that epigenetic regulation is a common plot linking the circadian clocks with addiction, though very little evidence has been reported to date. This review provides an elaborate overview of the circadian system and its involvement in addiction, and we hypothesise a possible connection at the epigenetic level that could further link them. Therefore, we think this review may further improve our understanding of the etiology or/and pathology of psychiatric disorders related to drug addiction.
Highlights
Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
It is catalysed by histone deacetylases (HDACs), which play an essential role in gene regulation, in part because the DNA becomes more tightly wrapped leading to reduced access to transcription factors and limited efficiency of RNA polymerase II
DNA methylation is a well-studied tissue-specific epigenetic modification considered to be important in gene regulation, generally by repressing gene transcription through recruitment of corepressor complexes (e.g., HDACs and histone demethylases (HDM)) involving several DNA methyl-binding domain proteins (MBDs) [75,76,77]
Summary
Epigenetics refers to the study of reversible, heritable changes in gene expression that do not involve changes in the DNA sequence [1]. Histone deacetylation is the reverse reaction to acetylation, where an acetyl group is removed It is catalysed by histone deacetylases (HDACs), which play an essential role in gene regulation, in part because the DNA becomes more tightly wrapped leading to reduced access to transcription factors and limited efficiency of RNA polymerase II elongation. While 5-methylcytosine generated by Dnmts has been considered as a fifth nucleotide in mammalian genomes [27], the discovery of its oxidative products (5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine) [22,24] has shown that this covalent DNA methylation modification was not as stable as initially thought This process is reversible through mechanisms involving ten-eleven translocation (Tets) methylcytosine dioxygenases and the base excision repair pathway [3,28]. MiRNAs have been considered as epigenetic modulators, forming a miRNA-epigenetic feedback loop that extensively impact on gene expression proliferation [31,32,33]
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