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Altered Huntingtin-Chromatin Interactions Predict Transcriptional and Epigenetic Changes in Huntingtons Disease

By Jocelynn R Pearl, Amol C. Shetty, Jeffrey P Cantle, Dani E Bergey, Robert M. Bragg, Sydney R. Coffey, Holly B Kordasiewicz, Leroy Hood, Nathan D Price, Seth A Ament, Jeffrey B Carroll

Posted 05 Jun 2020
bioRxiv DOI: 10.1101/2020.06.04.132571

Progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntingtons disease (HD), but direct relationships between the huntingtin (HTT) protein and chromatin remain poorly described. Here, using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that HTT reproducibly occupies specific locations in the mouse genome, including thousands of genomic loci that are differentially occupied in striatal tissue from a knock-in mouse model of HD (B6.HttQ111/+) versus wildtype controls. ChIP-seq of histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with trimethylation of histone 3 lysine 27 (H3K27me3), a repressive chromatin mark. Close to genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/+ vs. wildtype mice predicted increased H3K27me3, reduced histone 3 lysine 4 (H3K4me3, a marker of poised and active promoters), and down-regulated gene expression. Altered huntingtin-chromatin interactions may therefore play a direct role in driving transcriptional dysregulation in HD. ### Competing Interest Statement JBC has received research support from Ionis Pharmaceuticals, Wave Life Sciences, Triplet Therapeutics and consulting fees from Skyhawk Therapeutics and Guidepoint. JBC is a member of the scientific advisory board of Triplet Therapeutics. None of these companies had any role in the design or interpretations of these experiments. Other authors report no conflicts.

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