Characterization of the chromatin accessibility in Alzheimer’s disease

Abstract

Previous studies showed that the pathological hallmarks of Alzheimer’s disease (AD) are characterized by β‐amyloid(Aβ) deposition, neurofibrillary tangles, the upregulation of inflammation and neuronal apoptosis. However, the molecular mechanisms of most genes participated in the pathways above remained unclear. Gene expression is associated with the transcriptional level which is decided by the chromatin accessibility. In this study, the landscape of chromatin accessibility was described to disclose the outline of the transcriptions of AD‐associated metabolism and gene expression in an AD mouse model.The assay for transposase‐accessible chromatin by sequencing (ATAC‐seq) was utilized to investigate the AD‐associated chromatin reshaping in APPswe/PS1dE9 AD mouse model. The ATAC‐seq data in the hippocampus of 8‐month‐old APP/PS1 mice was generated and the relationship between the chromatin accessibility and the gene expressions was analyzed in combination with RNA‐seq. Gene ontology (GO) analysis and KEGG were applied to facilitate elucidating the alteration of biological process and signaling pathways. In addition, critical transcription factors were identified and, the alteration of the chromatin accessibility was further confirmed using ChIP assays.The genomic location distribution of peaks showed that the peaks distributed on the promoter‐TSS regions of APP/PS1 mice is significantly more than WT mice and, 1690 AD‐associated chromatin accessible regions in the hippocampus tissues of APP/PS1 mice were identified. These regions were enriched in the signaling pathways included PI3K‐Akt signaling pathway, Hippo signaling pathway, TGF‐β signaling pathway and Jak‐Stat signaling pathway which play essential roles in regulating of cell proliferation, cell apoptosis and inflammatory. GO analysis showed that many AD‐associated biological processes declined including cellular response to hyperoxia and insulin stimulus, synaptic transmission, and positive regulation of autophagy. 1090 genes were found to be up‐regulated, and 1081 genes were found to be down‐regulated in the hippocampus of the AD model mice. Interestingly, enhanced ATAC‐seq signal were found around 740 genes, of which 43 genes exhibited up‐regulated mRNA level. Several most significantly increased genes were also identified, including Sele, Clec7a, Cst7 and Ccr6 which critically involved in the development of AD. In addition, a great deal of transcription factors, including Olig2, NeuroD1, TCF4, NeuroG2 were found to enrich in the AD‐associated accessible chromatin regions. Besides, the transcription‐activating marks of H3K4me3 and H3K27ac were increased in the promoters of Sele, Clec7a, Cst7 and Ccr6 gene. These results above indicates that the mechanism for the up‐regulation genes could attribute to the enrichment of open chromatin regions by transcription factors and histone marks H3K4me3 and H3K27ac.Altogether, our study reveals that the alterations of chromatin accessibility might be an initial mechanism in AD pathogenesis.Support or Funding InformationThis work was supported by grants from the National Natural Science Foundation of China (No.81430037, No.81871714) and the Beijing Postdoctoral Sustentation Fund of China (No.ZZ2019‐13).ATAC‐seq chromatin accessibility analysis in hippocampus of Alzheimer’s disease (AD) model mice. A. Distribution of chromatin‐accessible regions across the genome in AD and WT mice. B. Signaling pathway associated with chromatin accessibility in AD mice. C. GO analysis of biological process associated with accessible chromatin regions in AD mice. D. Venn diagram showing genes associated with the chromatin‐accessible regions in AD and differentially‐expressed genes.Figure 1Motif enrichment and Histone modifications at the accessible chromatin regions. A. The 15 motifs with the greatest enrichment. B. The fold changes of histone H3K4me3 and H3K27ac are determined by ChIP‐qPCR, in chromatin‐accessible regions of SELE, Ccr6, CD300lf, Clec7a and Cst7 genes. Data are shown as mean ± SD. *p<0.05 and **p<0.01.Figure 2