Neuroepigenetic Mechanisms in Disease Michael A
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Christopher et al. Epigenetics & Chromatin (2017) 10:47 DOI 10.1186/s13072-017-0150-4 Epigenetics & Chromatin REVIEW Open Access Neuroepigenetic mechanisms in disease Michael A. Christopher1,2†, Stephanie M. Kyle1† and David J. Katz1* Abstract Epigenetics allows for the inheritance of information in cellular lineages during diferentiation, independent of changes to the underlying genetic sequence. This raises the question of whether epigenetic mechanisms also func- tion in post-mitotic neurons. During the long life of the neuron, fuctuations in gene expression allow the cell to pass through stages of diferentiation, modulate synaptic activity in response to environmental cues, and fortify the cell through age-related neuroprotective pathways. Emerging evidence suggests that epigenetic mechanisms such as DNA methylation and histone modifcation permit these dynamic changes in gene expression throughout the life of a neuron. Accordingly, recent studies have revealed the vital importance of epigenetic players in the central nervous system and during neurodegeneration. Here, we provide a review of several of these recent fndings, highlighting novel functions for epigenetics in the felds of Rett syndrome, Fragile X syndrome, and Alzheimer’s disease research. Together, these discoveries underscore the vital importance of epigenetics in human neurological disorders. Keywords: Neuroepigenetics, DNA methylation, Histone modifcation, Rett syndrome, Fragile X syndrome, Alzheimer’s disease, MECP2, FMR1, LSD1/KDM1A Introduction to neuroepigenetics neurons, and how is it established and maintained? Are Advances in molecular biology and genomics have allowed there consequences for misregulation of these processes researchers to uncover roles for epigenetic regulation in a that manifest in human disease? If so, it will be important diversity of biological processes previously unexplained by to determine the contribution of epigenetic mechanisms to classical genetics. Tese epigenetic mechanisms manifest complex diseases such as autism spectrum disorders (ASD) as a variety of chromatin modifcations and states, altering and neurodegenerative disorders, where identifcation of a gene function in a transient or persistent manner and act- purely genetic etiology has been elusive. In the frst part of ing as a vector for the passage of information. For example, this review, we introduce our current understanding of epi- considerable attention has been paid to the contributions of genetic modifcations, with an emphasis on what is known epigenetic aberrations during oncogenesis. In fact, epige- about them in post-mitotic neurons. In the second part of netic changes have been designated as one of the hallmarks this review, we highlight how disruption of these processes of cancer [1–3]. Oncogenic phenotypes can arise when an may contribute to three specifc examples of neurological insult or a mutation in an epigenetic pathway creates herit- disease. Importantly, this review is not intended as a com- able epigenetic information that is passaged through mito- prehensive summary of all that is known about neuroepi- sis. However, mature neurons no longer undergo mitosis genetics (for more information on neuroepigenetics, please and thus do not have an obligation to pass information see [4–6]. Rather, we hope that it will serve as an entry onto daughter cells. Tis makes the developed nervous point for researchers from multiple felds to begin to con- system an interesting system to study epigenetic regula- sider how post-mitotic neurons may have unique epige- tion. What epigenetic regulation is required in post-mitotic netic requirements, and how epigenetic mechanisms may contribute to neurological disease. *Correspondence: [email protected] †Michael A. Christopher and Stephanie M. Kyle contributed equally to this Epigenetic modifcations and their regulators work DNA methylation 1 Department of Cell Biology, Emory University School of Medicine, 615 One level of chromatin modifcation is the methylation Michael Street, Atlanta, GA 30322, USA Full list of author information is available at the end of the article of DNA at cytosine residues and, as recently discovered, © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Christopher et al. Epigenetics & Chromatin (2017) 10:47 Page 2 of 18 on adenosine residues. Given the size and complexity of Fan and colleagues have provided further evidence that the vertebrate genome, methylated DNA adds a layer of mature neurons require active maintenance of DNA regulation that further refnes the cellular transcriptional methylation. Te researchers showed that when both profle. Cytosine methylation in mammals occurs pri- Dnmt1 and Dnmt3a are deleted in post-mitotic excita- marily in a CpG dinucleotide context in most cell types. tory neurons, mice display learning and memory defcits It has been most extensively studied in the context of without neuronal loss. Tis phenotype only occurred CpG islands: genomic regions containing a higher rate when both methyltransferases were deleted, suggesting of CpG dinucleotides than the rest of the genome [7, 8]. that the enzymes redundantly regulate neuronal pro- Tese regions are thought to be evolutionarily conserved cesses in adult excitatory neurons. Hippocampi from regulatory elements, as CpGs are underrepresented in double Dnmt1/3a mutant animals displayed abnormal the genome due to spontaneous deamination of methyl- long-term potentiation following stimulation, suggest- cytosine into thymine, resulting in a T/G mismatch. ing the learning defcits are due to neuronal plasticity If this mismatch is not detected as a mutation by the errors. Genes involved in immune response, cell com- DNA repair pathway, it results in a C/G to T/A transi- munication, and mRNA transcriptional regulation were tion mutation in the resulting daughter strand [9]. Tus, also aberrantly expressed in double mutant mice brains preservation of CpGs at CpG islands is thought to occur due to hypomethylation of their promoter regions. Tis via positive selection at evolutionarily conserved promot- study demonstrates that the DNA methyltransferases ers. Cytosine methylation at CpG dinucleotides in pro- play redundant roles in post-mitotic neurons by regulat- moters is correlated with repressed transcription, while ing gene expression associated with neuronal homeosta- cytosine methylation in gene bodies, as well as meth- sis, which afects higher-order functions like learning and ylation of adenosines, appears to be correlated with an memory. Fan and colleague’s fndings suggest that DNA active transcriptional state in many cells [10–14]. A nota- demethylation occurs at promotor regions in the absence ble exception to this trend occurs within neurons, where of Dnmt1 and Dnmt3a [25]. Tis was surprising, as it cytosine methylation within gene bodies is anticorrelated suggests a role for Dnmt1, a methyltransferase that typi- with transcription [15, 16]. Cytosine methylation occurs cally transmits DNA methylation to daughter cells, in the by the addition of a methyl group to the ffth position of maintenance of DNA methylation in non-dividing adult the cytosine base (5mC) and is donated by S-adenosyl- neurons [25]. methionine. Tis reaction is carried out by DNA meth- Recently, some DNA demethylation by-products have yltransferase (DNMT) enzymes. DNMT3a and DNMT3b been described as biologically functional, suggesting can methylate cytosines de novo [17]. DNMT1 recog- that DNA methylation and demethylation are dynamic nizes palindromic hemimethylated CpG dinucleotides processes. 5mC can be oxidized to form 5-hydroxym- and adds a methyl group to the unmethylated cytosine on ethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-car- the opposite strand [18]. Trough the action of DNMT1, boxylcytosine (5caC) in sequential reactions carried out the maintenance methyltransferase, DNA methylation by the ten-eleven translocase (TET) family of enzymes can be inherited through DNA replication and cell divi- [26, 27]. Tis series of oxidation reactions is thought to sion, though it remains possible that DNMT1 has de be a mechanism of active demethylation, rather than one novo methyltransferase activity in certain contexts. of passive demethylation, which occurs through DNA However, this paradigm is challenged in the context of replication [28]. Te 5hmC mark is most highly enriched a post-mitotic neuron. Within the context of mature neu- in the brain when compared to any other tissue [29–31], rons, methylated CpG dinucleotides were once thought and TET1, which catalyzes the conversion of 5mC to to be very stable; however, DNA methylation is dynami- 5hmC, is activated by neuronal activity [19]. Current evi- cally regulated in the adult nervous system [19, 20]. Tis dence suggests that within the brain, 5hmC is acquired in mechanism is crucial in synaptic plasticity and memory a developmentally dependent manner, occurs exclusively formation [21, 22]. Specifcally, work from the Sweatt in the CpG context, and