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Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brainsстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 17 июня 2016 г.
- Авторы: Bai G., Cheung I., Shulha HP, Coelho JE, Li P., Dong X., Jakovcevski M., Wang Y., Grigorenko A., Jiang Y., Hoss A., Patel K., Zheng M., Rogaev E., Myers RH, Weng Z., Akbarian S., Chen JF
- Журнал: Human Molecular Genetics
- Том: 24
- Номер: 5
- Год издания: 2015
- Издательство: Oxford University Press
- Местоположение издательства: United Kingdom
- Первая страница: 1441
- Последняя страница: 1456
- DOI: 10.1093/hmg/ddu561
- Аннотация: To investigate epigenetic contributions to Huntington’s disease (HD) pathogenesis, we carried out genome-wide mapping of thetranscriptional mark, trimethyl-histone H3-lysine 4 (H3K4me3) in neuronal nuclei extracted from prefrontal cortex of HD casesand 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 neuronaldevelopment and neurodegeneration, including GPR3, TMEM106B, PDIA6 and the Notch signaling genes hairy and enhancer of split4 (HES4) and JAGGED2, supporting the view that the neuronal epigenome is affected in HD. Importantly, loss of H3K4me3 atCpG-rich sequences on the HES4 promoter was associated with excessive DNA methylation, reduced binding of nuclear proteinsto the methylated region and altered expression of HES4 and HES4 targeted genes MASH1 and P21 involved in striataldevelopment. Moreover, hypermethylation of HES4 promoter sequences was strikingly correlated with measures of striataldegeneration and age-of-onset in a cohort of 25 HD brains (r = 0.56, P = 0.006). Lastly, shRNA knockdown of HES4 in humanneuroblastoma cells altered MASH1 and P21 mRNA expression and markedly increased mutated HTT-induced aggregates andcell death. These findings, taken together, suggest that epigenetic dysregulation of HES4 could play a critical role in modifyingHD disease pathogenesis and severity
- Добавил в систему: Рогаев Евгений Иванович