Exercise Modifies the Transcriptional Regulatory Features of Monocytes in Alzheimer's Patients: A Multi-Omics Integration Analysis Based on Single Cell Technology.
Exercise Modifies the Transcriptional Regulatory Features of Monocytes in Alzheimer's Patients: A Multi-Omics Integration Analysis Based on Single Cell Technology.
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DOI：
10.3389/fnagi.2022.881488
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
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据报道，单核细胞是运动对阿尔茨海默病(AD)的保护作用的重要介质。本研究旨在探索单核细胞实现这一目标的机制。单细胞转录组分析结果表明，CD14+和CD16+单核细胞与循环血中其他细胞相互作用。研究发现，关键的配体受体相关基因--肿瘤坏死因子、CCR1、APP和AREG在运动治疗的AD患者和AD患者之间存在差异表达。进行场景分析以确定关键转录因子(TF)的单个簇。从共表达网络中获得了9个簇(M1-M9)。在已鉴定的转录因子中，MAFB、HES4和FOSL1在AD中有差异表达。此外，MAFB、HES4和FOSL1所属的M4簇被定义为AD表型的标志性簇。BulkRNA-seq差异分析显示，运动后肿瘤坏死因子、CCR1和APP的表达均上调(p<；0.05)。在M4簇中发现的ATF3、MAFB、HES4和KLF4可能是调节运动处方中的肿瘤坏死因子、CCR1和APP的因子。之后，APP、CCR1、肿瘤坏死因子、ATF3、KLF4、HES4和MAFB在ERADMT基因集中形成一个调控网络，并且它们都是机械连接的。ERADMT基因集已被发现是AD发生的潜在危险标志，并可作为AD患者运动治疗依从性的指标。利用单细胞整合分析，构建了AD患者单核细胞运动调节因子网络。构建的网络揭示了运动调节单核细胞对AD及其并发症的治疗效果的机制。然而，作为一项生物信息学研究，这项研究还需要进一步的实验验证。
Monocytes have been reported to be important mediators of the protective effect of exercise against the development of Alzheimer’s disease (AD). This study aims explored the mechanism by which monocytes achieve this. Using single cell transcriptome analysis, results showed that CD14 + and CD16 + monocytes interacted with other cells in the circulating blood. TNF, CCR1, APP, and AREG, the key ligand-receptor-related genes, were found to be differentially expressed between exercise-treated and AD patients. The SCENIC analysis was performed to identify individual clusters of the key transcription factors (TFs). Nine clusters (M1-M9) were obtained from the co-expression network. Among the identified TFs, MAFB, HES4, and FOSL1 were found to be differentially expressed in AD. Moreover, the M4 cluster to which MAFB, HES4, and FOSL1 belonged was defined as the signature cluster for AD phenotype. Differential analysis by bulkRNA-seq revealed that the expression of TNF, CCR1, and APP were all upregulated after exercise (p < 0.05). And ATF3, MAFB, HES4, and KLF4 that were identified in M4 clusters may be the TFs that regulate TNF, CCR1, and APP in exercise prescription. After that, APP, CCR1, TNF, ATF3, KLF4, HES4, and MAFB formed a regulatory network in the ERADMT gene set, and all of them were mechanistically linked. The ERADMT gene set has been found to be a potential risk marker for the development of AD and can be used as an indicator of compliance to exercise therapy in AD patients. Using single-cell integration analysis, a network of exercise-regulating TFs in monocytes was constructed for AD disease. The constructed network reveals the mechanism by which exercise regulated monocytes to confer therapeutic benefits against AD and its complications. However, this study, as a bioinformatic research, requires further experimental validation.
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