Clinical Laboratory of Xuanwu Hospital, Capital Medical University, Beijing, 100053, People's Republic of China.
Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People's Republic of China.
Alzheimers Res Ther. 2020 Mar 23;12(1):29. doi: 10.1186/s13195-020-00598-2.
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.
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.
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.
Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.
阿尔茨海默病（AD）的病理特征涉及与转录水平相关的众多基因表达的改变，这些改变是由染色质可及性决定的。在这里，研究了染色质可及性的图谱，以了解 AD 相关代谢基因在 AD 小鼠模型中的转录和表达概况。
使用转座酶可及染色质的测序（ATAC-seq）来研究 APPswe/PS1dE9（APP/PS1）小鼠模型中的 AD 相关染色质重塑。生成了 8 月龄 APP/PS1 小鼠海马体的 ATAC-seq 数据，并结合 RNA 测序分析了染色质可及性与基因表达之间的关系。应用基因本体论（GO）分析阐明了 APP/PS1 小鼠中改变的生物学过程和信号通路。鉴定了关键的转录因子；使用染色质免疫沉淀测定进一步证实了染色质可及性的改变。
我们在 APP/PS1 小鼠的海马组织中鉴定出 1690 个增加的 AD 相关染色质可及区域。这些区域富含与多种信号通路相关的基因，包括 PI3K-Akt、Hippo、TGF-β和 Jak-Stat 信号通路，它们在调节细胞增殖、凋亡和炎症反应中发挥着重要作用。总共鉴定出 1003 个减少的染色质可及区域，这些区域与 AD 相关的生物过程下降有关，包括细胞对高氧和胰岛素刺激的反应、突触传递和自噬的正调节。在 APP/PS1 海马体中，有 1090 个基因上调，1081 个基因下调。有趣的是，大约 740 个基因的 ATAC-seq 信号增强，其中 43 个基因的 mRNA 水平上调。与对照组相比，在 APP/PS1 小鼠中发现一些与 AD 发展相关的基因表达显著增加，包括 Sele、Clec7a、Cst7 和 Ccr6。在 AD 相关可及染色质区域中发现了包括 Olig2、NeuroD1、TCF4 和 NeuroG2 在内的许多转录因子的特征富集。在这些基因的启动子中也发现了转录激活标记 H3K4me3 和 H3K27ac 的增加。这些结果表明，基因上调的机制可能归因于具有转录因子基序和组蛋白标记 H3K4me3 和 H3K27ac 的开放染色质区域的富集。
我们的研究揭示了染色质可及性的改变可能是 AD 发病机制的初始机制。
