Article

Epigenetic Mechanisms in Neurological Disease

Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Nature medicine (Impact Factor: 28.05). 08/2012; 18(8):1194-204. DOI: 10.1038/nm.2828
Source: PubMed

ABSTRACT 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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    • "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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    • "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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