Altered huntingtin−chromatin interactions predict transcriptional and epigenetic changes in Huntington's disease

• Published in: Disease models & mechanisms Vol. 18; no. 5
• Main Authors: Pearl, Jocelynn R., Shetty, Amol C., Cantle, Jeffrey P., Bergey, Dani E., Bragg, Robert M., Coffey, Sydney R., Kordasiewicz, Holly B., Hood, Leroy E., Price, Nathan D., Ament, Seth A., Carroll, Jeffrey B.
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists 01.05.2025
• Subjects: Animals; chromatin; Chromatin - metabolism; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; epigenetics; Histones - metabolism; Humans; huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - genetics; huntington's disease; Mice; Protein Binding; Transcription, Genetic; Epigenetics; Chromatin; Huntingtin; Huntington's disease
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.052282

While progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington's disease (HD), the mechanistic basis remains poorly understood. Using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that the huntingtin protein (HTT) reproducibly occupies specific locations in the mouse genome. Striatal HTT ChIP-seq peaks were enriched in coding regions of spiny projection neuron identity genes that were found to have reduced expression in HD patients and mouse models, and had reduced occupancy in expanded polyglutamine HTT knock-in mice (HttQ111/Q111). By contrast, HTT occupancy was depleted near genes that are upregulated in HD. ChIP-seq of striatal histone modifications revealed genotype-specific colocalization of HTT with active chromatin marks and enhancer of zeste homolog 2 (EZH2), a key enzymatic component of the PRC2 complex. In the vicinity of genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/Q111 vs wild-type mice was associated with increased EZH2 occupancy, increased H3K4me3 levels and decreased H3K27me3 levels. Our study suggests that HTT−chromatin interactions may play a role in organizing chromatin and promoting cell type-specific gene expression, with HTT occupancy predicting transcriptional dysregulation in HD.