title: Targeting H3K4 trimethylation in Huntington disease.
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.
authors.affiliation: Department of Psychiatry and Human Behavior and UCI Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
authors.forename: Malini
authors.initials: M
authors.lastname: Vashishtha
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ng
authors.forename: Ferah
authors.initials: F
authors.lastname: Yildirim
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Gipson
authors.forename: Ian H
authors.initials: IH
authors.lastname: Kratter
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bodai
authors.forename: Wan
authors.initials: W
authors.lastname: Song
authors.forename: Alice
authors.initials: A
authors.lastname: Lau
authors.forename: Adam
authors.initials: A
authors.lastname: Labadorf
authors.forename: Annie
authors.initials: A
authors.lastname: Vogel-Ciernia
authors.forename: Juan
authors.initials: J
authors.lastname: Troncosco
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.forename: David E
authors.initials: DE
authors.lastname: Housman
authors.forename: Ernest
authors.initials: E
authors.lastname: Fraenkel
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C086055:HTT protein, human; D006657:Histones; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D056466:Histone Demethylases; C490173:Kdm5c protein, mouse; D010089:Oxidoreductases, N-Demethylating; D008239:Lysine
keywords: neurodegeneration; polyglutamine