title: Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models.
abstract: Transcriptional dysregulation plays a major role in the pathology of Huntington's disease (HD). However, the mechanisms causing selective downregulation of genes remain unknown. Histones regulate chromatin structure and thereby control gene expression; recent studies have demonstrated a therapeutic role for histone deacetylase (HDAC) inhibitors in polyglutamine diseases. This study demonstrates that despite no change in overall acetylated histone levels, histone H3 is hypo-acetylated at promoters of downregulated genes in R6/2 mice, ST14a and STHdh cells, as demonstrated by in vivo chromatin immunoprecipitation. In addition, HDAC inhibitor treatment increases association of acetylated histones with downregulated genes and corrects mRNA abnormalities. In contrast, there is a decrease in mRNA levels in wild-type cells following treatment with a histone acetyltransferase inhibitor. Although changes in histone acetylation correlate with decreased gene expression, histone hypo-acetylation may be a late event, as no hypo-acetylation is observed in 4-week-old R6/2 mice. Nevertheless, treatment with HDAC inhibitors corrects mRNA abnormalities through modification of histone proteins and may prove to be of therapeutic value in HD.
authors.affiliation: Department of Neurology, MassGeneral Institute for NeurodegenerativeDisease, Massachusetts General Hospital, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
authors.forename: Bérengère
authors.initials: B
authors.lastname: Bouzou
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Benn
authors.forename: Mee-Ohk
authors.initials: MO
authors.lastname: Kim
authors.forename: Prianka
authors.initials: P
authors.lastname: Chawla
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Overland
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Glajch
authors.forename: Eva
authors.initials: E
authors.lastname: Xia
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Qiu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hersch
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Clark
authors.forename: George J
authors.initials: GJ
authors.lastname: Yohrling
authors.forename: Jang-Ho J
authors.initials: JH
authors.lastname: Cha
mesh_terms: D000107:Acetylation; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D006657:Histones