Medium spiny neurons (MSNs) of the striatum are among the most vulnerable cell populations in Huntington's disease (HD). While transcriptional dysregulation in MSNs is a hallmark of HD, transcriptional studies to date have relied upon analysis of mixed cellular populations, which may obscure observation of transcriptional changes. To address this problem, we applied the cell type-specific translating ribosome affinity purification (TRAP) methodology, to the study of a mouse model of HD. We identify many previously unreported cell type-specific changes to gene expression in MSNs. In a search for regulators of the transcriptional response observed, we find that polycomb repressive complex 2 (PRC2) complex activity is altered in MSNs, and is predicted to account for most of the transcriptional repression observed in our study. Finally, we show that experimentally increasing PRC2-dependent H3K27me3 levels in wild-type striatum recapitulates behavior and molecular phenotypes characteristic of HD.