Neuroepigenetics

Abstract

Genome-wide DNA methylation patterns significantly change during brain development and maturation and are the basis for neuronal plasticity. Widespread methylome reconfiguration, such as non-CG methylation (mCH), occurs in neurons, but not in glial cells, during fetal to young adult development and becomes the dominant form of methylation in the human neuronal genome. In parallel, during brain development, there is an increase of 5hmC marks and possibly CpG demethylation in particular at gene bodies.

Rapid and dynamic methylation and demethylation of specific genes in the brain may play a fundamental role in learning, memory formation, and behavioral plasticity. MeCP2 is the best-characterized methyl-binding transcription factor and is involved both in gene activation and repression. MeCP2 is highly expressed in the brain and an important component of neuronal chromatin, where it reduces – via replacing the linker histone H1 – the chromatin repeat length to 165 bp. Mutations in the MECP2 gene are the mechanistic basis of the autism spectrum disorder Rett syndrome. In addition, also the histone acetylation level in neurons contributes to the cell’s proper function. Accordingly, KDAC inhibitors offer an effective therapy in neurodegenerative diseases, such as Rubinstein-Taybi syndrome, Friedreich ataxia and Huntington disease, in which the homeostasis of this epigenetic mark is disturbed. The transcription factor REST (RE1-silencing transcription factor) acts as DNA-binding platform for a large number of chromatin modifiers, such as KDACs, KMTs and KDMs, and primarily mediates silencing of its neuronal target genes. Dys-regulation of REST provides insight into epigenetic processes in the context of Alzheimer and Huntington diseases.

In this chapter, we will describe the field of neuroepigenetics and will provide mechanistic explanations for the contribution of epigenetics to neurodevelopmental and neurodegenerative diseases.