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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.

SUBMITTER: Bai G

PROVIDER: S-EPMC4321450 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Bai Guang G Cheung Iris I Shulha Hennady P HP Coelho Joana E JE Li Ping P Dong Xianjun X Jakovcevski Mira M Wang Yumei Y Grigorenko Anastasia A Jiang Yan Y Hoss Andrew A Patel Krupal K Zheng Ming M Rogaev Evgeny E Myers Richard H RH Weng Zhiping Z Akbarian Schahram S Chen Jiang-Fan JF

Human molecular genetics 20141205 5

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 n ...[more]

PMID: 25480889

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Project description:Peroxisome proliferator-activated receptor gamma (PPAR?) is a master regulator for white adipocyte differentiation and lipid storage. The increased level of hepatic PPAR?2 isoform reprograms liver for lipid storage and causes abnormal fat accumulation in certain pathophysiologic conditions. The current study aimed to investigate a role of transcriptional repressor hairy and enhancer of split 6 (HES6) in the regulation of Pparg2 expression and hepatic steatosis induced by diet. Liver-specific overexpression of Hes6 using adenovirus reduced Pparg2 messenger RNA levels by 90% and hepatic triglyceride accumulation by 22% compared to the levels in mice injected with an adenoviral empty vector with Western diet feeding. In sharp contrast, silencing Hes6 gene expression using short hairpin RNA increased hepatic lipid accumulation and Pparg2 messenger RNA levels by 70% and 4-fold, respectively. To locate hepatocyte nuclear factor 4 alpha (HNF4?) binding site(s), through which repressional activity of HES6 is mediated, a 2.5-kb Pparg2 promoter-driven luciferase reporter was constructed for transient transfection assays. Subsequently, chromatin immunoprecipitation and electrophoretic mobility shift assays were performed. An HNF4? binding consensus sequence was identified at 903 base pairs upstream from the transcription start site of Pparg2. Deletion or point mutation of the sequence in a luciferase reporter containing the Pparg2 promoter abolished HNF4?-mediated activation in HeLa cells. Chromatin immunoprecipitation and electrophoretic mobility shift assays further confirmed direct recruitment and binding of HNF4? to the site. Gene expression analysis with liver samples from subjects with nonalcoholic steatohepatitis suggested that the axis of the Hes6-Hnf4a-Pparg2 transcriptional cascade is also responsible for hepatic fat accumulation in humans. Conclusion: HES6 represses Pparg2 gene expression, thereby preventing hepatic lipid accumulation induced by chronic Western diet feeding or pathophysiologic conditions. (Hepatology Communications 2017;1:1085-1098).

Dataset Information

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

Publications

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

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