Abstract
Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity.
Highlights
DNA methylation and modifications of histones are part of molecular mechanisms that control gene expression promoting the stabilization of the genome as well (Almeida et al, 2017; Bauer and Martin, 2017; Kim and Kaang, 2017; Pasculli et al., 2018)
Despite significant advances have been achieved by studying the molecular role of histones in regulating health conditions, no direct evidence was available regarding the influence of histone methylation/demethylation activity on neurobiological phenomena such as the sleep-wake cycle and sleep-related neurochemicals
We described that histone methylation inhibition by deazaneplanocin A (DZNep) enhanced waking if injected during the lights-on period whereas histone demethylation inhibition by GSK-J1 caused a sleep-inducing effect if administered during the lights-off period
Summary
DNA methylation and modifications of histones are part of molecular mechanisms that control gene expression promoting the stabilization of the genome as well (Almeida et al, 2017; Bauer and Martin, 2017; Kim and Kaang, 2017; Pasculli et al., 2018). Understanding the molecular mechanism by which histone methylation/demethylation is translated into molecular modulators is essential to developing medicinal approaches for disease genetics and genome-related medicine. The histone methylation/demethylation activity is a promising target for exploring therapeutical options to treating multiple disorders. It has been demonstrated the role of histones in neurodegenerative diseases, aging, learning and memory (Jêsko et al, 2017; Kaluski et al, 2017; Zhao et al, 2018). The rationale use of histone methylation/demethylation inhibitors represents potential utility of DZNep or GSK-J1 in the comprehension of the role of histones in neurobiological processes, such as the sleep-wake cycle. We investigated the behavioral and neurochemical consequences that result from systemic injections of DZNep or GSK-J1, in the sleep-wake cycle and extracellular levels of monoamines, adenosine and acetylcholine in rats
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