Epigenetic Mechanisms in Neurological Disease

Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Nature medicine (Impact Factor: 27.36). 08/2012; 18(8):1194-204. DOI: 10.1038/nm.2828
Source: PubMed


The exploration of brain epigenomes, which consist of various types of DNA methylation and covalent histone modifications, is providing new and unprecedented insights into the mechanisms of neural development, neurological disease and aging. Traditionally, chromatin defects in the brain were considered static lesions of early development that occurred in the context of rare genetic syndromes, but it is now clear that mutations and maladaptations of the epigenetic machinery cover a much wider continuum that includes adult-onset neurodegenerative disease. Here, we describe how recent advances in neuroepigenetics have contributed to an improved mechanistic understanding of developmental and degenerative brain disorders, and we discuss how they could influence the development of future therapies for these conditions.

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    • "Methylation of histones also influences transcription by attracting chromatin-modifying enzymes but, unlike acetylation, can either promote or repress transcription depending on the site and number of histone methylations. For example, H3K27/ 9me3 is a repressive mark, whereas H3K4me and H4K12ac promote a transcriptionally active state (Jakovcevski and Akbarian 2012). Histones can also be phosphorylated on a number of residues , and this is usually associated with transcriptional activity (Graff et al. 2011). "
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    ABSTRACT: Epigenetic processes in the brain involve the transfer of information arising from short-lived cellular signals and changes in neuronal activity into lasting effects on gene expression. Key molecular mediators of epigenetics include methylation of DNA, histone modifications, and noncoding RNAs. Emerging findings in animal models and human brain tissue reveal that epilepsy and epileptogenesis are associated with changes to each of these contributors to the epigenome. Understanding and influencing the molecular mechanisms controlling epigenetic change could open new avenues for treatment. DNA methylation, particularly hypermethylation, has been found to increase within gene body regions and interference with DNA methylation in epilepsy can change gene expression profiles and influence epileptogenesis. Posttranscriptional modification of histones, including transient as well as sustained changes to phosphorylation and acetylation, have been reported, which appear to influence gene expression. Finally, roles have emerged for noncoding RNAs in brain excitability and seizure thresholds, including microRNA and long noncoding RNA. Together, research supports strong effects of epigenetics influencing gene expression in epilepsy, suggesting future therapeutic approaches to manipulate epigenetic processes to treat or prevent epilepsy.
    Cold Spring Harbor Perspectives in Medicine 10/2015; DOI:10.1101/cshperspect.a022731 · 9.47 Impact Factor
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    • "Histones and their numerous posttranslational modifications (PTMs) are fundamental to the process of cell fate decision making and organismal development. Consistent with this, studies have shown that both histone mutation and PTM misregulation contribute to the initiation and progression of a wide number of human diseases, including cancer and neurological disorders (Bannister and Kouzarides, 2011; Dawson and Kouzarides, 2012; Funato et al., 2014; Jakovcevski and Akbarian, 2012; Lewis et al., 2013; Rothbart and Strahl, 2014). Histone modifications function in part as docking sites for effector proteins harboring specialized, evolutionarily conserved domains that ''read'' the single or combinatorial modification states of histones (Gardner et al., 2011; Jenuwein and Allis, 2001; Strahl and Allis, 2000). "
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    ABSTRACT: Access to high-quality antibodies is a necessity for the study of histones and their posttranslational modifications (PTMs). Here we debut the Histone Antibody Specificity Database (, an online and expanding resource cataloging the behavior of widely used, commercially available histone antibodies by peptide microarray. This interactive web portal provides a critical resource to the biological research community that routinely uses these antibodies as detection reagents for a wide range of applications. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 07/2015; 59(3). DOI:10.1016/j.molcel.2015.06.022 · 14.02 Impact Factor
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    • "However, chromatin modifications and possibly other epigenetic signals appear to have dedicated roles in the adult brain. Mutations in several known epigenetic regulators cause neurological phenotypes (Jakovcevski and Akbarian, 2012), and at least in the case of the methyl-cytosine binding protein MeCP2 it was demonstrated that the gene contributes to the phenotype in the adult brain (Luikenhuis et al., 2004), suggesting a functional – rather than developmental – role. The culprit for this connection might be DNA methylation, because its levels respond dynamically to brain activity (Guo et al., 2011), and because its potential for long-term memory of transcriptional states resonates with the need for the long-term stability of neuronal states necessary for higher brain function. "
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    ABSTRACT: Epigenetics studies the emergence of different phenotypes from a single genotype. Although these processes are essential to cellular differentiation and transcriptional memory, they are also widely used in all branches of the tree of life by organisms that require plastic but stable adaptation to their physical and social environment. Because of the inherent flexibility of epigenetic regulation, a variety of biological phenomena can be traced back to evolutionary adaptations of few conserved molecular pathways that converge on chromatin. For these reasons chromatin biology and epigenetic research have a rich history of chasing discoveries in a variety of model organisms, including yeast, flies, plants and humans. Many more fascinating examples of epigenetic plasticity lie outside the realm of model organisms and have so far been only sporadically investigated at a molecular level; however, recent progress on sequencing technology and genome editing tools have begun to blur the lines between model and non-model organisms, opening numerous new avenues for investigation. Here, I review examples of epigenetic phenomena in non-model organisms that have emerged as potential experimental systems, including social insects, fish and flatworms, and are becoming accessible to molecular approaches. © 2015. Published by The Company of Biologists Ltd.
    Journal of Experimental Biology 01/2015; 218(Pt 1):114-122. DOI:10.1242/jeb.110809 · 2.90 Impact Factor
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