Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.04.132571v1?rss=1 Authors: Pearl, J. R., Shetty, A. C., Cantle, J. P., Bergey, D. E., Bragg, R. M., Coffey, S. R., Kordasiewicz, H. B., Hood, L. E., Price, N. D., Ament, S. A., Carroll, J. B. Abstract: 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. Copy rights belong to original authors. Visit the link for more info