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dc.contributor.authorBai, Guang
dc.contributor.authorCheung, Iris
dc.contributor.authorShulha, Hennady P.
dc.contributor.authorCoelho, Joana E.
dc.contributor.authorLi, Ping
dc.contributor.authorDong, Xianjun
dc.contributor.authorJakovcevski, Mira
dc.contributor.authorWang, Yumei
dc.contributor.authorGrigorenko, Anastasia
dc.contributor.authorJiang, Yan
dc.contributor.authorHoss, Andrew
dc.contributor.authorPatel, Krupal
dc.contributor.authorZheng, Ming
dc.contributor.authorRogaev, Evgeny
dc.contributor.authorMyers, Richard H.
dc.contributor.authorWeng, Zhiping
dc.contributor.authorAkbarian, Schahram
dc.contributor.authorChen, Jiang-Fan
dc.date2022-08-11T08:07:59.000
dc.date.accessioned2022-08-23T15:38:18Z
dc.date.available2022-08-23T15:38:18Z
dc.date.issued2015-03-01
dc.date.submitted2015-06-24
dc.identifier.citationHum Mol Genet. 2015 Mar 1;24(5):1441-56. doi: 10.1093/hmg/ddu561. Epub 2014 Dec 5. <a href="http://dx.doi.org/10.1093/hmg/ddu561">Link to article on publisher's site</a>
dc.identifier.issn0964-6906 (Linking)
dc.identifier.doi10.1093/hmg/ddu561
dc.identifier.pmid25480889
dc.identifier.urihttp://hdl.handle.net/20.500.14038/25907
dc.description.abstractTo 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=25480889&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1093/hmg/ddu561
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectBioinformatics
dc.subjectComputational Biology
dc.subjectIntegrative Biology
dc.subjectSystems Biology
dc.titleEpigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains
dc.typeJournal Article
dc.source.journaltitleHuman molecular genetics
dc.source.volume24
dc.source.issue5
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bioinformatics_pubs/49
dc.identifier.contextkey7256008
html.description.abstract<p>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.</p>
dc.identifier.submissionpathbioinformatics_pubs/49
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.source.pages1441-56


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