Epigenetic regulation in Huntington's disease.

Huntington's disease (HD) is a devastating and fatal monogenic neurodegenerative disorder characterized by progressive loss of selective neurons in the brain and is caused by an abnormal expansion of CAG trinucleotide repeats in a coding exon of the huntingtin (HTT) gene. Progressive gene expression changes that begin at premanifest stages are a prominent feature of HD and are thought to contribute to disease progression. Increasing evidence suggests the critical involvement of epigenetic mechanisms in abnormal transcription in HD. Genome-wide alterations of a number of epigenetic modifications, including DNA methylation and multiple histone modifications, are associated with HD, suggesting that mutant HTT causes complex epigenetic abnormalities and chromatin structural changes, which may represent an underlying pathogenic mechanism. The causal relationship of specific epigenetic changes to early transcriptional alterations and to disease pathogenesis require further investigation. In this article, we review recent studies on epigenetic regulation in HD with a focus on DNA and histone modifications. We also discuss the contribution of epigenetic modifications to HD pathogenesis as well as potential mechanisms linking mutant HTT and epigenetic alterations. Finally, we discuss the therapeutic potential of epigenetic-based treatments.