The Role of H3K9 Acetylation and Gene Expression in Different Brain Regions of Alzheimer’s Disease Patients

Abstract

Aims: To evaluate H3K9 acetylation and gene expression profiles in three brain regions of Alzheimer’s disease (AD) patients and elderly controls, and to identify AD region-specific abnormalities. Methods: Brain samples of auditory cortex, hippocampus and cerebellum from AD patients and controls underwent chromatin immunoprecipitation sequencing, RNA sequencing and network analyses. Results: We found a hyperacetylation of AD cerebellum and a slight hypoacetylation of AD hippocampus. The transcriptome revealed differentially expressed genes in the hippocampus and auditory cortex. Network analysis revealed Rho GTPase-mediated mechanisms. Conclusions: These findings suggest that some crucial mechanisms, such as Rho GTPase activity and cytoskeletal organization, are differentially dysregulated in brain regions of AD patients at the epigenetic and transcriptomic levels, and might contribute toward future research on AD pathogenesis.

Plain language summary

Alzheimer’s disease (AD) is the most common form of dementia affecting the elderly population. The onset and progression of AD are influenced by environmental factors, which are able to promote epigenetic changes on the DNA and/or the DNA-associated proteins called histones. We investigated a specific epigenetic modification of histones (H3K9 acetylation) in three brain regions of AD patients and compared them with elderly controls. We found increased levels of H3K9 acetylation in the cerebellum of AD patients, as well as a slight decrease of this modification in the hippocampus of the same patients. These brain tissues from AD patients showed abnormal gene expression patterns when compared with elderly controls. These findings contribute to understanding the molecular changes that occur in AD, and provide a basis for future research or drug development for AD treatment.

Keywords: :

• aging
• Alzheimer’s disease
• ChIP-seq
• histone modification
• RNA-seq

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0096

Author contributions

D Santana and E Chen designed the research study; E Chen and M Smith obtained funding for the research; G Turecki and N Mechawar managed, classified and provided all the samples from the Douglas–Bell Canada Brain Bank; D Santana conducted the chromatin immunoprecipitation and generated all the ChIP-Seq and RNA-Seq libraries; C Gigek participated in the chromatin immunoprecipitation steps; T Faria extracted all the RNA samples; S Payao conducted APOE genotyping; R Puga, A Bedrat and B Lemos were responsible for the bioinformatics analyses; D Santana conducted the Gene Ontology and the network analyses; E Chen supervised the research; D Santana led the manuscript drafting with critical input from all coauthors. All authors contributed to the writing, editing and/or review of the manuscript and approved the submission.

Acknowledgments

The authors would like to thank the patients and their families for donating the brains for research and the Douglas–Bell Canada Brain Bank for classifying and providing the samples that made this study possible.

Financial&competing interests disclosure

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The Douglas–Bell Canada Brain Bank (DBCBB) is partly funded by Healthy Brains for Healthy Lives (CFREF) and Brain Canada Platform Grants to G Turecki and N Mechawar. The DBCBB is also funded by the Réseau Québécois sur le suicide, le troubles de l’humeur et les troubles associés (FRQ-S). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

All procedures performed in this study were conducted in accordance with the ethical standards of the Ethics Committee of McGill University and Universidade Federal de São Paulo (UNIFESP/EPM) – 823.722. Informed consent was obtained from the families of all individual participants included in the study.

Data sharing statement

The raw data that support the findings of this study are available from the corresponding author on request.

Additional information

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The Douglas–Bell Canada Brain Bank (DBCBB) is partly funded by Healthy Brains for Healthy Lives (CFREF) and Brain Canada Platform Grants to G Turecki and N Mechawar. The DBCBB is also funded by the Réseau Québécois sur le suicide, le troubles de l’humeur et les troubles associés (FRQ-S). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.