title: Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains.
abstract: To investigate epigenetic contributions to Huntington's disease (HD) pathogenesis, we carried out genome-wide mapping of the transcriptional mark, trimethyl-histone H3-lysine 4 (H3K4me3) in neuronal nuclei extracted from prefrontal cortex of HD cases and controls using chromatin immunoprecipitation followed by deep-sequencing. Neuron-specific mapping of the genome-wide distribution of H3K4me3 revealed 136 differentially enriched loci associated with genes implicated in neuronal development and neurodegeneration, including GPR3, TMEM106B, PDIA6 and the Notch signaling genes hairy and enhancer of split 4 (HES4) and JAGGED2, supporting the view that the neuronal epigenome is affected in HD. Importantly, loss of H3K4me3 at CpG-rich sequences on the HES4 promoter was associated with excessive DNA methylation, reduced binding of nuclear proteins to the methylated region and altered expression of HES4 and HES4 targeted genes MASH1 and P21 involved in striatal development. Moreover, hypermethylation of HES4 promoter sequences was strikingly correlated with measures of striatal degeneration and age-of-onset in a cohort of 25 HD brains (r = 0.56, P = 0.006). Lastly, shRNA knockdown of HES4 in human neuroblastoma cells altered MASH1 and P21 mRNA expression and markedly increased mutated HTT-induced aggregates and cell death. These findings, taken together, suggest that epigenetic dysregulation of HES4 could play a critical role in modifying HD disease pathogenesis and severity.
authors.affiliation: Department of Neural and Pain Sciences, University of Maryland Dental School, Baltimore, MD 21201, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Bai
authors.affiliation: Brudnick Neuropsychiatric Research Institute.
authors.forename: Iris
authors.initials: I
authors.lastname: Cheung
authors.affiliation: Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Hennady P
authors.initials: HP
authors.lastname: Shulha
authors.affiliation: Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Joana E
authors.initials: JE
authors.lastname: Coelho
authors.affiliation: Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Dong
authors.affiliation: Brudnick Neuropsychiatric Research Institute.
authors.forename: Mira
authors.initials: M
authors.lastname: Jakovcevski
authors.affiliation: Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Brudnick Neuropsychiatric Research Institute.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Grigorenko
authors.affiliation: Friedman Brain Institute, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hoss
authors.affiliation: Department of Neural and Pain Sciences, University of Maryland Dental School, Baltimore, MD 21201, USA.
authors.forename: Krupal
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Neural and Pain Sciences, University of Maryland Dental School, Baltimore, MD 21201, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Brudnick Neuropsychiatric Research Institute.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Rogaev
authors.affiliation: Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA, Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.affiliation: Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Friedman Brain Institute, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA, chenjf@bu.edu.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000328:Adult; D001344:Autopsy; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D056426:Genetic Loci; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010802:Phylogeny; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005819:Genetic Markers; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000072056:Transcription Factor HES-1; C065500:ASCL1 protein, human; C078493:HES1 protein, human