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

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.

doi:10.1101/2020.06.04.132571

bioRxiv · 10.1101/2020.06.04.132571

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

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.

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Abstract

Progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntingtons disease (HD), but 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. Moreover, many genomic loci were differentially occupied by HTT in striatal tissue from a homozygous knock-in mouse model of HD (B6.HttQ111/Q111) when compared to wildtype controls. Huntingtin ChIP-seq peaks were enriched in the coding regions of cell identity genes important for striatal function, with many of these genes found to have reduced expression in the striata of HD patients and mouse models, as well as reduced HTT occupancy in HttQ111/Q111mice compared to controls. Conversely, HTT ChIP-seq peaks were depleted near genes that are up-regulated in HD. ChIP-seq of bulk striatal histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with active chromatin marks (H3K4me3 and H3K27ac), and with enhancer of zeste homolog 2 (EZH2), a key enzymatic component of the PRC2 complex. Near genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/Q111 vs. wildtype mice was associated with increased EZH2 binding, increased histone H3 lysine 4 (H3K4me3), and decreased histone H3 lysine 27 (H3K27me3). Our study suggests that huntingtin-chromatin interactions may play a direct role in organizing chromatin and promoting cell type-specific gene expression, with loss of HTT occupancy predicting decreased gene expression in HD.

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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.. 2020-06-05. Altered Huntingtin-Chromatin Interactions Predict Transcriptional and Epigenetic Changes in Huntingtons Disease. https://doi.org/10.1101/2020.06.04.132571

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