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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    • "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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    • "Therefore, we also examined DNA methylation in the nuclear genome. We measured nuclear 5-hydroxymethylation (5hmC), an emerging alternative methylation marker, as well as 5mC methylation at the left end of rat L1Rn (long interspersed repeated), a marker of methylation in retrotransposons, the 'jumping' DNA sequences that have been shown to have key roles in neuronal plasticity (Jakovcevski and Akbarian 2012). To further understand neuronal epigenetic PBDE toxicity, we measured changes in the DNA methylation of nuclear candidate genes related to behavioral and brain functions. "
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    ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are known endocrine disrupting chemicals used commonly as flame retardants in everything from electronics to furniture. Exposure to PBDEs during early development has been linked to neurodevelopmental delays. Despite mounting evidence of neurological harm from PBDE exposure, the molecular mechanisms underlying these effects on brain function remain unknown. We examined the effects of perinatal exposure to BDE-47, the most biologically active and prevalent BDE congener in North America, on epigenetic patterns in the frontal lobe of Wistar rats. Dams were gavaged with BDE-47 (0.002 and 0.2 mg/kg body weight) at gestation days 9 and 16, and postnatal days 1, 8, and 15. Frontal lobes from offspring at postnatal day 41 were collected to measure 5-methylcytosine (5mC) in mitochondrial cytochrome c oxidase genes (Mt-co1, Mt-co2, and Mt-co3), global nuclear 5-hydroxymethylcytosine (5hmC) content, 5mC in repetitive elements L1Rn, and 5mC in nuclear genes (Bdnf, Crhr1, Mc2r, Nr3c1, and Snca) related to behavioral and brain functions in the nuclear genome. We observed a significant decrease in %5mC in Mt-co2 (difference from control = −0.68%, p = 0.01 at the 0.2 mg/kg BDE-47). 5mC in repetitive elements L1Rn decreased at 0.002 mg/kg BDE-47 (difference = −1.23%, p = 0.02). Decreased nuclear 5mC was observed in Bdnf and Nr3c1 in BDE-47 exposed rats. However, we did not observe significant effects of PBDE toxicity on DNA methylation patterns for the majority of genes in the brain.
    Toxicology 12/2014; DOI:10.1016/j.tox.2014.12.019 · 3.62 Impact Factor
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    • "DNA methylation is an important methylation reaction, involving addition of a methyl groups at CpG sites on DNA, and it is a major factor for epigenetic-based changes in gene expression. In recent studies, abnormal DNA methylation patterns have been implicated in schizophrenia [17] [18] and ASD [19] [20], but more prominently in the latter. Rett syndrome, immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome and autosomal dominant cerebellar ataxia are few examples of a heterogeneous group of neurodegenerative and neurodevelopmental disorders caused by changes in proteins that either " read " or " write " DNA methylation, resulting in disordered DNA methylation at numerous single-copy genes as well as in specific sequences of repeat DNA in parts of constitutive heterochromatin [17]. "
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    ABSTRACT: Dietary interventions like gluten-free and casein-free diets have been reported to improve intestinal, autoimmune and neurological symptoms in patients with a variety of conditions; however, the underlying mechanism of benefit for such diets remains unclear. Epigenetic programming, including CpG methylation and histone modifications, occurring during early postnatal development can influence the risk of disease in later life, and such programming may be modulated by nutritional factors such as milk and wheat, especially during the transition from a solely milk-based diet to one that includes other forms of nutrition. The hydrolytic digestion of casein (a major milk protein) and gliadin (a wheat-derived protein) releases peptides with opioid activity, and in the present study, we demonstrate that these food-derived proline-rich opioid peptides modulate cysteine uptake in cultured human neuronal and gastrointestinal (GI) epithelial cells via activation of opioid receptors. Decreases in cysteine uptake were associated with changes in the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine. Bovine and human casein-derived opioid peptides increased genome-wide DNA methylation in the transcription start site region with a potency order similar to their inhibition of cysteine uptake. Altered expression of genes involved in redox and methylation homeostasis was also observed. These results illustrate the potential of milk- and wheat-derived peptides to exert antioxidant and epigenetic changes which may be particularly important during the postnatal transition from placental to GI nutrition. Differences between peptides derived from human and bovine milk may contribute to developmental differences between breastfed and formula-fed infants. Restricted antioxidant capacity, caused by wheat- and milk-derived opioid peptides, may predispose susceptible individuals to inflammation and systemic oxidation, partly explaining the benefits of gluten-free or casein-free diets.
    The Journal of Nutritional Biochemistry 10/2014; 25(10). DOI:10.1016/j.jnutbio.2014.05.004 · 3.79 Impact Factor
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