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    Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains

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    Authors
    Bai, Guang
    Cheung, Iris
    Shulha, Hennady P.
    Coelho, Joana E.
    Li, Ping
    Dong, Xianjun
    Jakovcevski, Mira
    Wang, Yumei
    Grigorenko, Anastasia
    Jiang, Yan
    Hoss, Andrew
    Patel, Krupal
    Zheng, Ming
    Rogaev, Evgeny
    Myers, Richard H.
    Weng, Zhiping
    Akbarian, Schahram
    Chen, Jiang-Fan
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    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Program in Bioinformatics and Integrative Biology
    Document Type
    Journal Article
    Publication Date
    2015-03-01
    Keywords
    Biochemistry, Biophysics, and Structural Biology
    Bioinformatics
    Computational Biology
    Integrative Biology
    Systems Biology
    
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    Link to Full Text
    http://dx.doi.org/10.1093/hmg/ddu561
    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.
    Source
    Hum Mol Genet. 2015 Mar 1;24(5):1441-56. doi: 10.1093/hmg/ddu561. Epub 2014 Dec 5. Link to article on publisher's site
    DOI
    10.1093/hmg/ddu561
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/25907
    PubMed ID
    25480889
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1093/hmg/ddu561
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    Program in Bioinformatics and Integrative Biology Publications

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