Targeting H3K4 trimethylation in Huntington disease.

Vashishtha M, Ng CW, Yildirim F, Gipson TA, Kratter IH, Bodai L, Song W, Lau A, Labadorf A, Vogel-Ciernia A, Troncosco J, Ross CA, Bates GP, Krainc D, Sadri-Vakili G, Finkbeiner S, Marsh JL, Housman DE, Fraenkel E, Thompson LM.

Abstract

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.

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