Ma Yanzhen, Li Weizu, Fan Chang, Wang Yongzhong, Jiang Hui, Yang Wenming
Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China.
Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, Anhui, China.
J Alzheimers Dis. 2022;90(4):1659-1675. doi: 10.3233/JAD-220564.
N4-acetylcytidine (ac4C), an important posttranscriptional modification, is involved in various disease processes. Long noncoding RNAs (lncRNAs) regulate gene expression mainly through epigenetic modification, transcription, and posttranscriptional modification. Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloidosis of the brain. However, the role of lncRNA ac4C modification in AD remains unclear.
In this study, we investigated the association between ac4C modification and AD, and the underlying mechanisms of ac4C modification in AD.
The male 9-month-old APP/PS1 double transgenic mice, age- and sex-matched wild type (WT) mice were used in this study. Then, ac4C-RIP-seq and RNA-seq were used to comprehensively analyze lncRNA ac4C modification in AD mice. The lncRNA-miRNA-mRNA regulatory networks using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed the regulatory relationships among these three lncRNAs and AD.
The results showed that there were 120 significantly different ac4C peaks located on 102 lncRNAs in AD, of which 55 were hyperacetylated and 47 were hypoacetylated. Simultaneously, 231 differentially expressed lncRNAs were identified, including 138 upregulated lncRNAs and 93 downregulated lncRNAs. Moreover, 3 lncRNAs, lncRNA Gm26508, lncRNA A430046D13Rik, and lncRNA 9530059O14Rik, showed significant changes in both the ac4C and RNA levels using conjoint analysis.
The abundance of lncRNA ac4C modification is significantly different in AD and indicates that lncRNA ac4C is associated with the occurrence and development of AD, which could provide a basis for further exploration of the related regulatory mechanisms.
N4-乙酰胞苷（ac4C）是一种重要的转录后修饰，参与多种疾病进程。长链非编码RNA（lncRNA）主要通过表观遗传修饰、转录及转录后修饰来调控基因表达。阿尔茨海默病（AD）是一种以脑淀粉样变性为特征的神经退行性疾病。然而，lncRNA的ac4C修饰在AD中的作用尚不清楚。
在本研究中，我们探究了ac4C修饰与AD之间的关联以及ac4C修饰在AD中的潜在机制。
本研究使用了9月龄雄性APP/PS1双转基因小鼠以及年龄和性别匹配的野生型（WT）小鼠。然后，采用ac4C-RIP-seq和RNA-seq全面分析AD小鼠中lncRNA的ac4C修饰情况。利用基因本体论（GO）、京都基因与基因组百科全书（KEGG）通路分析构建lncRNA- miRNA- mRNA调控网络，以显示这三种lncRNA与AD之间的调控关系。
结果显示，AD中有120个位于102个lncRNA上的显著不同的ac4C峰，其中55个为高乙酰化，47个为低乙酰化。同时，鉴定出231个差异表达的lncRNA，包括138个上调的lncRNA和93个下调的lncRNA。此外，联合分析显示，lncRNA Gm26508、lncRNA A430046D13Rik和lncRNA 9530059O14Rik这3个lncRNA的ac4C和RNA水平均有显著变化。
AD中lncRNA的ac4C修饰丰度存在显著差异，表明lncRNA的ac4C与AD的发生发展相关，这可为进一步探索相关调控机制提供依据。
