B11 Altered epigenetic signature in the striatum of HD mice and patients

Epigenetic alterations are documented in several models of Huntington’s disease (HD). However, it remains unclear whether similar alterations also occur in HD patients. Using the striatum of HD R6/1 mice and genome-wide approaches, we found that down-regulated genes display a particular epigenetic signature and this signature is altered in HD mouse striatum. We showed that H3K27ac signal is selectively decreased at super-enhancers, a category of enhancers regulating cell-type specific genes. Our results suggest that the mechanism linking epigenetic and transcriptional defects in HD striatum involves altered expression of non-coding RNA expressed from super-enhancers (seRNAs). To assess whether the mechanism is conserved in HD patients, we generated H3K27ac ChIP-seq data from the striatum of HD patients and control individuals. Our results indicate that striatal super-enhancer signature is also altered in HD patients. Together, our data support a model where altered epigenetic regulation of super-enhancers would be responsible for gene down-regulation in HD brain tissues. We suggest that targeting enhancer activity may be of therapeutic interest.