Epigenome signatures landscaped by histone H3K9me3 are associated with the synaptic dysfunction in Alzheimer's disease

Min Young Lee, Junghee Lee, Seung Jae Hyeon, Hyesun Cho, Yu Jin Hwang, Jong Yeon Shin, Ann C. McKee, Neil W. Kowall, Jong Il Kim, Thor D. Stein, Daehee Hwang, Hoon Ryu

Research output: Contribution to journalArticle

Abstract

The pathogenesis of Alzheimer's disease (AD) and the commonest cause of dementia in the elderly remain incompletely understood. Recently, epigenetic modifications have been shown to play a potential role in neurodegeneration, but the specific involvement of epigenetic signatures landscaped by heterochromatin has not been studied in AD. Herein, we discovered that H3K9me3-mediated heterochromatin condensation is elevated in the cortex of sporadic AD postmortem brains. In order to identify which epigenomes are modulated by heterochromatin, we performed H3K9me3-chromatin immunoprecipitation (ChIP)-sequencing and mRNA-sequencing on postmortem brains from normal subjects and AD patients. The integrated analyses of genome-wide ChIP- and mRNA-sequencing data identified epigenomes that were highly occupied by H3K9me3 and inversely correlated with their mRNA expression levels in AD. Biological network analysis further revealed H3K9me3-landscaped epigenomes to be mainly involved in synaptic transmission, neuronal differentiation, and cell motility. Together, our data show that the abnormal heterochromatin remodeling by H3K9me3 leads to down-regulation of synaptic function-related genes, suggesting that the epigenetic alteration by H3K9me3 is associated with the synaptic pathology of sporadic AD.

Original languageEnglish
Article numbere13153
JournalAging Cell
Volume19
Issue number6
DOIs
StatePublished - 1 Jun 2020

Keywords

  • Alzheimer's disease
  • epigenetic modifications
  • genome-wide sequencing
  • histone H3K9me3
  • synaptic transmission

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    Lee, M. Y., Lee, J., Hyeon, S. J., Cho, H., Hwang, Y. J., Shin, J. Y., McKee, A. C., Kowall, N. W., Kim, J. I., Stein, T. D., Hwang, D., & Ryu, H. (2020). Epigenome signatures landscaped by histone H3K9me3 are associated with the synaptic dysfunction in Alzheimer's disease. Aging Cell, 19(6), [e13153]. https://doi.org/10.1111/acel.13153