Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains
Authors
Bai, GuangCheung, 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
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyProgram in Bioinformatics and Integrative Biology
Document Type
Journal ArticlePublication Date
2015-03-01Keywords
Biochemistry, Biophysics, and Structural BiologyBioinformatics
Computational Biology
Integrative Biology
Systems Biology
Metadata
Show full item recordAbstract
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 siteDOI
10.1093/hmg/ddu561Permanent Link to this Item
http://hdl.handle.net/20.500.14038/25907PubMed ID
25480889Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1093/hmg/ddu561