title: Modulation of nucleosome dynamics in Huntington's disease.
abstract: Transcriptional dysregulation and aberrant chromatin remodeling are central features in the pathology of Huntington's disease (HD). In order to more fully characterize these pathogenic events, an assessment of histone profiles and associated gene changes were performed in transgenic N171-82Q (82Q) and R6/2 HD mice. Analyses revealed significant chromatin modification, resulting in reduced histone acetylation with concomitant increased histone methylation, consistent with findings observed in HD patients. While there are no known interventions that ameliorate or arrest HD progression, DNA/RNA-binding anthracyclines may provide significant therapeutic potential by correcting pathological nucleosome changes and realigning transcription. Two such anthracyclines, chromomycin and mithramycin, improved altered nucleosome homeostasis in HD mice, normalizing the chromatin pattern. There was a significant shift in the balance between methylation and acetylation in treated HD mice to that found in wild-type mice, resulting in greater acetylation of histone H3 at lysine 9 and promoting gene transcription. Gene expression profiling in anthracycline-treated HD mice showed molecular changes that correlate with disease correction, such that a subset of downregulated genes were upregulated with anthracycline treatment. Improved nucleosomal dynamics were concurrent with a significant improvement in the behavioral and neuropathological phenotype observed in HD mice. These data show the ability of anthracycline compounds to rebalance epigenetic histone modification and, as such, may provide the rationale for the design of human clinical trials in HD patients.
authors.affiliation: Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, MA 01730, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Del Signore
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Byoung Y
authors.initials: BY
authors.lastname: Soh
authors.forename: Darlene R
authors.initials: DR
authors.lastname: Goldstein
authors.forename: Samantha
authors.initials: S
authors.lastname: Matson
authors.forename: Sarah
authors.initials: S
authors.lastname: Goodrich
authors.forename: Angela L
authors.initials: AL
authors.lastname: Markey
authors.forename: Kerry
authors.initials: K
authors.lastname: Cormier
authors.forename: Sean W
authors.initials: SW
authors.lastname: Hagerty
authors.forename: Karen
authors.initials: K
authors.lastname: Smith
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
mesh_terms: D000107:Acetylation; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002865:Chromomycins / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008745:Methylation; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism*; D008926:Plicamycin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002865:Chromomycins; D006657:Histones; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009707:Nucleosomes; D008926:Plicamycin