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Review
. 2012 Aug;18(8):1194-204.
doi: 10.1038/nm.2828.

Epigenetic mechanisms in neurological disease

Affiliations
Review

Epigenetic mechanisms in neurological disease

Mira Jakovcevski et al. Nat Med. 2012 Aug.

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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Figures

Figure 1
Figure 1. The epigenome and chromatin organization
The top part shows that chromosomes are organized into domains of loose (euchromatin) or highly condensed (heterochromatin) chromatin and other loosely defined higher order structures (such as ‘globules’), some of which are tethered to the nuclear membrane. The bottom part shows 11 nm ‘beads-on-a-string’ chromatin fiber comprised of nucleosomal arrays connected by linker DNA, and linker histones as major regulators of nucleosomal repeat length. The distribution of DNA methylation and a small subset of > 100 posttranslational histone markings, linker histones and core histone variants represents differential regulation at (left) active promoters and gene bodies as opposed to enhancers, or (right) silenced and repressed chromatin, as indicated.
Figure 2
Figure 2. Example monogenetic brain disorders with a heterochromatin defect
Three examples of monogenetic brain disorders associated with defects in heterochromatin are shown. Mutations in genes encoding the histone demethylase DNMT3B (associated with the disorder ICF1) or the transcriptional repressor ZBTB24 (associated with the disorder ICF2) result in hypo(DNA mC5) methylation of different types of pericentric satellite repeats,. The multifunctional chromatin regulator ATRX controls the incorporation of the variant histone H3.3 not only just into nucleosomes surrounding the transcription start sites of active genes but also at various repeat sequences, as indicated. Loss of function mutations in ATRX have been associated with various X-linked mental retardation syndromes.

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