The Role of Histone Acetylation in the Pathophysiology of Huntington's Disease

In recent years the epigenetic regulation of gene expression through histone modifications has come to light as an important mechanism of transcriptional control. Transcriptional dysregulation is a key feature in Huntington’s disease (HD), an autosomal dominant neurodegenerative disorder characterized by problems with movement, cognition, and behavioral functioning. Previous work from our group has demonstrated that post-translational modifications of histone proteins are altered in multiple cellular and animal models of HD. Specifically acetylated histone H3 association with the promoters of downregulated genes is decreased in the presence of mutant huntingtin. In addition, chromatin immunoprecipitation followed by microarray hybridization (ChIP-on-chip) indicated that there is a significant decrease in the levels of acetylated histone H3 at gene loci in a transgenic mouse model of HD. More importantly, treatment of cellular and animal models of HD with histone deacetylase (HDAC) inhibitors reversed the decrease in acetylated histone binding to gene promoters and normalized mRNA levels for the downregulated genes. Together, our findings demonstrate that histone acetylation is altered in HD and provides evidence for the role for HDAC inhibitors as potential novel therapeutic agents for the treatment of neurodegenerative diseases. Our current efforts are aimed at identifying novel HDAC inhibitors for the treatment of HD.