title: RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression.
abstract: Huntington's Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480) of the 28,087 confidently detected genes are differentially expressed (FDR<0.05) and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes), that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti-inflammatory therapeutics may offer important opportunities in treating HD.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.|Bioinformatics Program, Boston University, Boston, MA, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Labadorf
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Hoss
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lagomarsino
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Tiffany C
authors.initials: TC
authors.lastname: Hadzi
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Joli
authors.initials: J
authors.lastname: Bregu
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Friedman Brain Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, United States of America.|Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, United States of America.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America.|Bioinformatics Program, Boston University, Boston, MA, United States of America.|Genome Science Institute, Boston University School of Medicine, Boston, MA, United States of America.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D050437:Genes, Developmental; D005801:Genes, Homeobox; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D007249:Inflammation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017423:Sequence Analysis, RNA / Q000379:methods*