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.