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. 2020 Mar 23;12(1):29.
doi: 10.1186/s13195-020-00598-2.

Characterization of the chromatin accessibility in an Alzheimer's disease (AD) mouse model

Yaqi Wang  1 , Xiaomin Zhang  1 , Qiao Song  1 , Yuli Hou  1 , Jing Liu  1 , Yu Sun  2 , Peichang Wang  3
Affiliations

Characterization of the chromatin accessibility in an Alzheimer's disease (AD) mouse model

Yaqi Wang et al. Alzheimers Res Ther. .

Abstract

Background: 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. 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.

Methods: The 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.

Results: We 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.

Conclusion: Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.

Keywords: ATAC-seq; Alzheimer’s disease; Chromatin accessibility; RNA-seq; Transcription factors.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
ATAC-seq chromatin accessibility analysis in hippocampus of Alzheimer’s disease (AD) model mice and wild type (WT) mice. a Distribution of ATAC-seq fragment size in AD and WT mice. b Density plot showing the position of THSSs in AD and WT mice. The left dashed line indicates the putative promoter region located 1 kb upstream. c Chromatin accessibility around the TSS in AD and WT mice. d Annotation of THSSs to genomic features: Exons, intergenic regions, introns, promoters, and TTS. THSSs located up to 1 kb upstream of the ATG are determined as promoter regions. e Representative distribution of chromatin-accessible regions across the genome in AD and WT mice. f The percentage of annotate peaks on promoter region in AD and WT mice. Data are shown as mean ± SD. *p < 0.05
Fig. 2
Fig. 2
Pathway analysis and Gene Ontology (GO) analysis in AD mice. a Signaling pathway associated with chromatin accessibility in AD mice. b GO analysis of biological process associated with accessible chromatin regions in AD mice. c GO analysis of cellular component associated with chromatin-accessible regions in AD mice
Fig. 3
Fig. 3
The association between the AD-specific chromatin-accessible regions and gene expression in AD mice. a ATAC-seq signal at TSSs correlates quantitatively with gene expression, the left figures (in blue) show the correlation between ATAC-seq signal at TSS and gene expression in AD mice, and the right figures (in pink) show the correlation between ATAC-seq signal at TSS and gene expression in WT mice. b Volcano plot of differentially expressed genes in AD, upregulated genes are shown by red dots and downregulated genes are shown by blue dots. c Venn diagram showing genes associated with the chromatin-accessible regions in AD and differentially expressed genes. d Upregulated genes in AD that are associated with AD-specific open chromatin regions. e Downregulated genes in AD that are associated with AD-specific closed chromatin regions
Fig. 4
Fig. 4
RNA-seq gene expression analysis in the hippocampus of AD and WT mice. a Heatmap of 50 most variable genes are listed based on RNA-seq. b Changes in chromatin accessibility downstream of the APP gene. Track in blue shows normalized and input-corrected ATAC-seq signal in WT mice and track in red shows normalized and input-corrected ATAC-seq signal in APP/PS1 mice. The chromatin-accessible regions are indicated with blue bars (WT mice) or red bars (AD mice) on the middle area of the graph and the TSS is shown by blue arrow
Fig. 5
Fig. 5
Gene enrichment in signaling pathways and GO analysis. a Upregulated gene enrichment in signaling pathways (20 most enrichment signaling pathways are listed). b Downregulated gene enrichment in signaling pathways (20 most enrichment signaling pathways are listed). c Upregulated gene enrichment in biological process (20 most enrichment biological process are listed). d Downregulated gene enrichment in biological process (20 most enrichment biological process are listed). The rich factor is defined as the ratio of the number of differential genes enriched in the pathway to the number of annotated genes
Fig. 6
Fig. 6
Motif enrichment at chromatin-accessible regions in AD mice. a Heatmap of 50 most enrichment ATAC-seq peaks at accessible chromatin regions. b The 15 motifs with the greatest enrichment. c Tracks for AD sample at the APP, GSAP, and SORL1 genes with predicted TCF4 binding sites. The predicted TCF4 binding sites are shown with orange bars on the upper areas of the tracks. The TSS is indicated by blue arrow
Fig. 7
Fig. 7
Histone modifications at the accessible chromatin regions. 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
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