Page 85 - Q. Neuroscience

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

Abstract Introduction

The pathogenesis of Alzheimer's disease (AD) and the commonest  Alzheimer's disease (AD), the most common progressive neurodegenerative
cause of dementia in the elderly remain incompletely understood. disease, is the leading cause of dementia in the elderly.
Recently, epigenetic modifications have been shown to play a potential
role in neurodegeneration, but the specific involvement of epigenetic  Although there are genetic effects on the pathogenesis of familial AD, most AD
signatures landscaped by heterochromatin has not been studied in AD. cases are not familial and do not have a simple genetic cause suggesting that
Herein, we discovered that H3K9me3-mediated heterochromatin environmental factors are important to AD pathogenesis.
condensation is elevated in the cortex of sporadic AD postmortem  Recently, histone modifications, DNA methylation, ribosomal DNAs (rDNAs), and
brains. In order to identify which epigenomes are modulated by microRNAs (miRNAs) have been suggested as epigenetic factors mediating the
heterochromatin, we performed H3K9me3-chromatin influence of environmental factors on AD-related gene expression.
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 Aims of Study
identified epigenomes that were highly occupied by H3K9me3 and
inversely correlated with their mRNA expression levels in AD. Biological Hypothesis: Abnormal heterochromatin remodeling by
network analysis further revealed H3K9me3- landscaped epigenomes to H3K9me3 is linked to down-regulation of synaptic function-
be mainly involved in synaptic transmission, neuronal differentiation, related genes in sporadic AD.
and cell motility. Together, our data show that the abnormal Aim 1: To examine whether H3K9me3- dependent
heterochromatin remodeling by H3K9me3 leads to down-regulation of heterochromatin remodeling is altered.
synaptic function related genes, suggesting that the epigenetic
alteration by H3K9me3 is associated with the synaptic pathology of Aim 2: To investigate which H3K9me3-associated epigenome
sporadic AD. signatures are associated with the pathogenesis of sporadic
KEY WORDS: Alzheimer's disease, epigenetic modifications, genome- AD.
wide sequencing, histone H3K9me3, synaptic transmission
Results

1. H3K9me3-dependent heterochromatin is altered in the AD 4. Integratedanalysisofgenome-wideChIP-andmRNA- 6. H3K9me3-landscapedand synaptic function-related transcriptome are
sequencingidentifiesalterationsofH3K9me3- deregulated in AD.
enrichedtranscriptomes in AD.

2. H3K9me3isdifferentiallymarkedinAD

5. AnetworkmodelshowsthatalterationofH3K9me3- Conclusion
landscapedepigenomeislinkedtoasystematicderegulationofAD-
related processes.
Conclusion:
integrated analysis of H3K9me3-ChIP- sequencing and RNA-
sequencing data disclosed changes affecting a list of
3. Transcriptome is differentially expressed in AD
epigenomes involved in synaptic transmission, neuronal
differentiation, and cell motility in AD. Our findings suggest that
H3K9me3 is intimately involved in the systematic epigenetic
alter-ations found in AD and that H3K9me3-landscaped genes
are associ-ated with AD pathogenesis.
Acknowledgements:
This study was also supported by the National Research Foundation of Korea Grant
(NRF-2018M3C7A1056894 and NRF-2016M3C7A1904233) from the Ministry of
Science, ICT and Future Planning, the National Research Council of Science &
Technology (NST) Grant (No. CRC- 15-04-KIST) from the Korea government
(MSIP), and Grants from Korea Institute of Science and Technology (2E30320 and
2E30762). This study was supported by NIH Grant (R01NS067283 and AG054156
to H.R. and T.S.; R01 NS109537 to J.L.).