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      Sleep Deprivation and the Epigenome

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          Abstract

          Sleep deprivation disrupts the lives of millions of people every day and has a profound impact on the molecular biology of the brain. These effects begin as changes within a neuron, at the DNA and RNA level, and result in alterations in neuronal plasticity and dysregulation of many cognitive functions including learning and memory. The epigenome plays a critical role in regulating gene expression in the context of memory storage. In this review article, we begin by describing the effects of epigenetic alterations on the regulation of gene expression, focusing on the most common epigenetic mechanisms: (i) DNA methylation; (ii) histone modifications; and (iii) non-coding RNAs. We then discuss evidence suggesting that sleep loss impacts the epigenome and that these epigenetic alterations might mediate the changes in cognition seen following disruption of sleep. The link between sleep and the epigenome is only beginning to be elucidated, but clear evidence exists that epigenetic alterations occur following sleep deprivation. In the future, these changes to the epigenome could be utilized as biomarkers of sleep loss or as therapeutic targets for sleep-related disorders.

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          Most cited references71

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          DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation.

          In conjunction with histone modifications, DNA methylation plays critical roles in gene silencing through chromatin remodeling. Changes in DNA methylation perturb neuronal function, and mutations in a methyl-CpG-binding protein, MeCP2, are associated with Rett syndrome. We report that increased synthesis of brain-derived neurotrophic factor (BDNF) in neurons after depolarization correlates with a decrease in CpG methylation within the regulatory region of the Bdnf gene. Moreover, increased Bdnf transcription involves dissociation of the MeCP2-histone deacetylase-mSin3A repression complex from its promoter. Our findings suggest that DNA methylation-related chromatin remodeling is important for activity-dependent gene regulation that may be critical for neural plasticity.
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            Circadian regulator CLOCK is a histone acetyltransferase.

            The molecular machinery that governs circadian rhythmicity comprises proteins whose interplay generates time-specific transcription of clock genes. The role of chromatin remodeling in a physiological setting such as the circadian clock is yet unclear. We show that the protein CLOCK, a central component of the circadian pacemaker, has histone acetyltransferase (HAT) activity. CLOCK shares homology with acetyl-coenzyme A binding motifs within the MYST family of HATs. CLOCK displays high sequence similarity to ACTR, a member of SRC family of HATs, with which it shares also enzymatic specificity for histones H3 and H4. BMAL1, the heterodimerization partner of CLOCK, enhances HAT function. The HAT activity of CLOCK is essential to rescue circadian rhythmicity and activation of clock genes in Clock mutant cells. Identification of CLOCK as a novel type of DNA binding HAT reveals that chromatin remodeling is crucial for the core clock mechanism and identifies unforeseen links between histone acetylation and cellular physiology.
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              ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation.

              Members of the ING family of tumor suppressors regulate cell cycle progression, apoptosis, and DNA repair as important cofactors of p53. ING1 and ING3 are stable components of the mSin3A HDAC and Tip60/NuA4 HAT complexes, respectively. We now report the purification of the three remaining human ING proteins. While ING2 is in an HDAC complex similar to ING1, ING4 associates with the HBO1 HAT required for normal progression through S phase and the majority of histone H4 acetylation in vivo. ING5 fractionates with two distinct complexes containing HBO1 or nucleosomal H3-specific MOZ/MORF HATs. These ING5 HAT complexes interact with the MCM helicase and are essential for DNA replication to occur during S phase. Our data also indicate that ING subunits are crucial for acetylation of chromatin substrates. Since INGs, HBO1, and MOZ/MORF contribute to oncogenic transformation, the multisubunit assemblies characterized here underscore the critical role of epigenetic regulation in cancer development.
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                Author and article information

                Contributors
                Journal
                Front Neural Circuits
                Front Neural Circuits
                Front. Neural Circuits
                Frontiers in Neural Circuits
                Frontiers Media S.A.
                1662-5110
                27 February 2018
                2018
                : 12
                : 14
                Affiliations
                [1]Department of Molecular Physiology and Biophysics, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa , Iowa City, IA, United States
                Author notes

                Edited by: Paul J. Shaw, School of Medicine, Washington University in St. Louis, United States

                Reviewed by: Sushil K. Jha, Jawaharlal Nehru University, India; Matthew Thimgan, Missouri University of Science and Technology, United States

                *Correspondence: Ted Abel ted-abel@ 123456uiowa.edu
                Article
                10.3389/fncir.2018.00014
                5835037
                29535611
                f358adfd-b3c0-4da2-b94b-ec467c34c4e9
                Copyright © 2018 Gaine, Chatterjee and Abel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 August 2017
                : 29 January 2018
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 101, Pages: 10, Words: 8512
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R01 MH 099544, P50 AG 017628
                Categories
                Neuroscience
                Review

                Neurosciences
                sleep deprivation,dna methylation,histone modifications,micrornas,long non-coding rna

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