Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Nucleic Acids Res. 2022 Nov 28;50(21):12497-12514. doi: 10.1093/nar/gkac1107.
RNA is modified by hundreds of chemical reactions and folds into innumerable shapes. However, the regulatory role of RNA sequence and structure and how dysregulation leads to diseases remain largely unknown. Here, we uncovered a mechanism where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We found an enhancer RNA, AANCR, that regulates the transcription and expression of apolipoprotein E (APOE). In some human cells such as fibroblasts, AANCR is folded into an R-loop and modified by N-glycosidic cleavage; in this form, AANCR is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in other cell types including hepatocytes and under stress, AANCR does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length enhancer that promotes APOE expression. DNA sequence variants in AANCR are associated significantly with APOE expression and Alzheimer's Disease, thus AANCR is a modifier of Alzheimer's Disease. Besides AANCR, thousands of noncoding RNAs are regulated by abasic sites in R-loops. Together our data reveal the essentiality of the folding and modification of RNA in cellular regulation and demonstrate that dysregulation underlies common complex diseases such as Alzheimer's disease.
RNA 经历了数百种化学反应的修饰，并折叠成无数种形状。然而，RNA 序列和结构的调节作用以及失调如何导致疾病在很大程度上仍然未知。在这里，我们揭示了一种机制，即 R 环中的 RNA 脱碱基位点通过使 RNA 聚合酶 II 暂停来调节转录。我们发现了一种增强子 RNA，AANCR，它调节载脂蛋白 E (APOE) 的转录和表达。在某些人类细胞（如成纤维细胞）中，AANCR 折叠成 R 环并被 N-糖苷键切割修饰；在这种形式下，AANCR 是一个部分转录的无功能增强子，APOE 不表达。相比之下，在其他细胞类型（包括肝细胞）和应激下，AANCR 不会形成稳定的 R 环，因为其序列未被修饰，因此被转录成全长增强子，促进 APOE 表达。AANCR 中的 DNA 序列变异与 APOE 表达和阿尔茨海默病显著相关，因此 AANCR 是阿尔茨海默病的修饰因子。除了 AANCR，数千种非编码 RNA 也受到 R 环中脱碱基位点的调节。我们的数据共同揭示了 RNA 折叠和修饰在细胞调节中的重要性，并表明失调是阿尔茨海默病等常见复杂疾病的基础。
