Epigenetic regulation in Huntington's disease

Abstract

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.

Keywords: DNA methyltransferases (DNMTs); Epigenetic regulation; Epigenetic-based therapy; Huntington's disease (HD); Neurodegeneration; Transcription.

Fig. 1.

A model for DNA methylation-mediated gene repression in HD. Schematic shows potential players involved in promoter hypermethylation and transcriptional repression in HD neurons. Mutant HTT (mHTT) expression increases the levels of DNA methylation at specific gene promoters, including Bdnf exon IV promoter in cortical neurons (Pan et al., 2016). Dnmt1/DNMT3A-mediated promoter methylation contributes to transcriptional repression of genes important for neuronal function and survival, leading to neuronal dysfunction and death (Pan et al., 2016). Methyl-CpG-binding protein MeCP2 binds to methylated DNA and recruits epigenetic modifiers, including HDAC, to repress transcription. DNMT1 and DNMT3A may also interact with HDACs (Fuks et al., 2001; Rountree et al., 2000). mHTT directly binds to MeCP2 and enhances binding of MeCP2 to Bdnf exon IV promoter, leading to downregulation of Bdnf (McFarland et al., 2014). In cancer, Polycomb repressive complex 2 (PRC2) core subunit EZH2 recruits DNMTs to specific gene promoters via direct interaction (Vire et al., 2006). Whether this mechanism occurs in HD neurons remains to be tested. Me, methylation (5mC).

Fig. 2.

Epigenetic dysregulation leading to neurodegeneration in HD. N-terminal mutant HTT exon 1 (mHTT ex1) fragments generated by aberrant splicing are highly pathogenic. mHTT ex1 causes changes in DNA methylation and histone modifications and alters chromatin structure. These changes induce transcriptional dysregulation and could also affect DNA repair and genomic stability, leading to neuronal dysfunction and death in HD. Epigenetic and transcriptional dysregulation in HD could alter expression of nuclearly encoded mitochondrial proteins essential for mitochondrial function and energy metabolism, leading to mitochondrial dysfunction. The direct action of mHTT on mitochondria also causes toxicity. Metabolic changes in HD mitochondria may affect the availability of cofactors for chromatin modifying enzymes, causing epigenetic dysregulation. Aging and environmental factors could influence epigenetic mechanisms. Inhibitors of epigenetic modifiers, including DNMTs and HDACs, may reverse mutant HTT-induced epigenetic and transcriptional alterations and block neurodegeneration.