Abstract
BackgroundThe pathological hallmarks of Alzheimer’s disease (AD) involve alterations in the expression of numerous genes associated with transcriptional levels, which are determined by chromatin accessibility. Here, the landscape of chromatin accessibility was studied to understand the outline of the transcription and expression of AD-associated metabolism genes in an AD mouse model.MethodsThe assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA sequencing. Gene ontology (GO) analysis was applied to elucidate biological processes and signaling pathways altered in APP/PS1 mice. Critical transcription factors were identified; alterations in chromatin accessibility were further confirmed using chromatin immunoprecipitation assays.ResultsWe identified 1690 increased AD-associated chromatin-accessible regions in the hippocampal tissues of APP/PS1 mice. These regions were enriched in genes related to diverse signaling pathways, including the PI3K-Akt, Hippo, TGF-β, and Jak-Stat signaling pathways, which play essential roles in regulating cell proliferation, apoptosis, and inflammatory responses. A total of 1003 decreased chromatin-accessible regions were considered to be related with declined AD-associated biological processes including cellular response to hyperoxia and insulin stimulus, synaptic transmission, and positive regulation of autophagy. In the APP/PS1 hippocampus, 1090 genes were found to be upregulated and 1081 downregulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting upregulated mRNA levels. Several genes involved in AD development were found to have a significantly increased expression in APP/PS1 mice compared to controls, including Sele, Clec7a, Cst7, and Ccr6. The signatures of numerous transcription factors, including Olig2, NeuroD1, TCF4, and NeuroG2, were found enriched in the AD-associated accessible chromatin regions. The transcription-activating marks of H3K4me3 and H3K27ac were also found increased in the promoters of these genes. These results indicate that the mechanism for the upregulation of genes could be attributed to the enrichment of open chromatin regions with transcription factors motifs and the histone marks H3K4me3 and H3K27ac.ConclusionOur study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.
Highlights
The pathological hallmarks of Alzheimer’s disease (AD) involve alterations in the expression of numerous genes associated with transcriptional levels, which are determined by chromatin accessibility
Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis
Chromatin accessibility by ATAC-seq is predictive of active transcription in Amyloid-beta precursor protein (APP)/PS1 mice As APP/PS1 mouse is a widely used animal model to study Alzheimer’s disease [33], we employed hippocampal tissues of APP/PS1 mice and age-matched wild type (WT) mice to generate ATAC-seq libraries
Summary
The pathological hallmarks of Alzheimer’s disease (AD) involve alterations in the expression of numerous genes associated with transcriptional levels, which are determined by chromatin accessibility. Alzheimer’s disease (AD), an age-associated chronic progressive neurodegenerative disorder, is characterized by progressive loss of memory, cognitive impairment, and behavioral changes. It is the most common form of dementia. The pathological hallmarks of AD are characterized by β-amyloid (Aβ) deposition, neurofibrillary tangles induced by phosphorylation of tau protein, upregulation of inflammation, and neuronal apoptosis All these processes involve alterations in the expression and regulation of numerous genes. Exploring the regulatory elements of AD genes and their corresponding transcription factors (TFs) is critically important for elucidation of the disease process
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