Page 86 - Q. Neuroscience

[Q. Neuroscience-52]

Epigenome signatures landscaped by histone H3K9me3 are

linked to the synaptic dysfunction in Alzheimer's disease

Seung Jae Hyeon¹, Min Young Lee², Hyesun Cho³, Yu Jin Hwang¹, Jong-Yeon Shin³, Ann C. McKee⁴˙⁵˙⁶,
Neil W. Kowall⁴˙⁵˙⁶, Jong-Il Kim³, Thor D. Stein⁴˙⁵˙⁶, Daehee Hwang⁷, Junghee Lee⁴˙⁵, Hoon Ryu¹˙⁵

¹Center for Neuroscience, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea, ²Systems

Biology, Institute for Systems Biology, Seattle 98109, USA, ³Biochemistry, Seoul National University College of
Medicine, Seoul 03080, Republic of Korea, ⁴Neurology, Veteran's Affairs Boston Healthcare System, Boston 02130,
USA, ⁵Neurology, Boston University Alzheimer’s Disease Center , Boston 02130, USA, ⁶Center for the Study of

Traumatic Encephalopathy, Boston University School of Medicine, Boston 02118, USA, ⁷Biological Sciences, Seoul

National University, Seoul 08826, Republic of Korea

The pathogenesis of Alzheimer's disease (AD) and the commonest cause of dementia in the elderly remains
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 shows 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 AD.