High-Throughput Sequencing to Investigate lncRNA-circRNA-miRNA-mRNA Networks Underlying the Effects of Beta-Amyloid Peptide and Senescence on Astrocytes.
High-Throughput Sequencing to Investigate lncRNA-circRNA-miRNA-mRNA Networks Underlying the Effects of Beta-Amyloid Peptide and Senescence on Astrocytes.
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DOI：
10.3389/fgene.2022.868856
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发表时间：
2022
影响因子：
3.7
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中科院分区：
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星形胶质细胞广泛分布于中枢神经系统，在神经元细胞的功能中起着至关重要的作用。星形胶质细胞与阿尔茨海默病（AD）之间的关联已经被注意到，最近的研究表明环状RNA （circRNA）和长链非编码RNA （lncRNA）参与了AD的发展。然而，关于lncRNA和circRNA究竟参与了β淀粉样蛋白（Aβ）和衰老对星形胶质细胞的影响，鲜有报道。因此，本研究在转录组水平上考察了Aβ和衰老对星形胶质细胞的影响。原代培养的星形胶质细胞经Aβ处理，体外培养90 d，高通量测序鉴定差异表达rna。基因本体和京都基因与基因组百科富集分析显示，差异表达基因与局灶黏附信号通路、细胞外基质受体信号通路和细胞外基质相关。构建蛋白-蛋白相互作用网络，筛选出103个枢纽基因；其中大多数与细胞外基质、细胞外基质受体信号通路和局灶黏附的表达密切相关。基于选择的中枢基因和差异RNA构建了两个竞争性内源RNA网络，并确定了多个竞争性内源RNA调控轴，这些调控轴参与了Aβ和衰老对星形胶质细胞的影响。本研究首次从全转录组角度探讨Aβ与衰老对初代星形胶质细胞的分子调控机制。通过揭示Aβ和衰老对星形胶质细胞影响的信号通路和生物学过程，本研究在竞争性内源性RNA网络调控水平上为AD的发病机制提供了新的见解。
Astrocytes are widely distributed in the central nervous system and play an essential role in the function of neuronal cells. Associations between astrocytes and Alzheimer’s disease (AD) have been noted, and recent work has implicated circular RNA (circRNA) and long non-coding RNA (lncRNA) in the development of AD. However, few reports have investigated which lncRNA and circRNA are involved in the influence of amyloid beta (Aβ) and senescence on astrocytes. This study therefore examines changes at the transcriptome level to explore the effects of Aβ and senescence on astrocytes. Primary cultured astrocytes were treated with Aβ and cultured for 90 days in vitro, and high-throughput sequencing was performed to identify differentially expressed RNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that differentially expressed genes were associated with the focal adhesion signaling pathway, extracellular matrix receptor signaling pathway, and the extracellular matrix. The protein–protein interaction network was then constructed, and 103 hub genes were screened out; most of these were strongly associated with the expression of the extracellular matrix, extracellular matrix receptor signaling pathway, and focal adhesion. Two competing endogenous RNA networks were constructed based on the selected hub gene and differential RNAs, and we identified multiple competing endogenous RNA regulatory axes that were involved in the effects of Aβ and senescence on astrocytes. This is the first study to explore the molecular regulation mechanism of Aβ and senescence on primary astrocytes from the perspective of the whole transcriptome. In uncovering the signaling pathways and biological processes involved in the effects of Aβ and senescence on astrocytes, this work provides novel insights into the pathogenesis of AD at the level of competing endogenous RNA network regulation.