CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China.
Nat Aging. 2021 May;1(5):438-453. doi: 10.1038/s43587-021-00056-0. Epub 2021 May 6.
The transcriptome undergoes global changes during aging, including both protein-coding and noncoding RNAs. Using comparative genomics, we identify aging-associated long noncoding RNAs (lncRNAs) that are under evolutionary constraint and are more conserved than lncRNAs that do not change with age. Aging-associated lncRNAs are enriched for functional elements, including binding sites for RNA-binding proteins and transcription factors, in particular nuclear factor kappa B (NFκB). Using CRISPR screening, we discovered that 13 of the aging-associated lncRNAs were regulators of the NFκB pathway, and we named this family 'NFκB modulating aging-related lncRNAs (NFKBMARLs)'. Further characterization of NFκBMARL-1 reveals it can be traced to 29 Ma before humans and is induced by NFκB during aging, inflammation and senescence. Reciprocally, NFκBMARL-1 directly regulates transcription of the NFκB inhibitor NFKBIZ in cis within the same topologically associated domain by binding to the NFKBIZ enhancer and recruiting RELA to the NFKBIZ promoter. These findings reveal many aging-associated lncRNAs are evolutionarily conserved components of the NFκB pathway.
转录组在衰老过程中会发生全局变化，包括蛋白质编码和非编码 RNA。通过比较基因组学，我们确定了与衰老相关的长链非编码 RNA（lncRNA），这些 lncRNA 受到进化约束，比不随年龄变化的 lncRNA 更为保守。与衰老相关的 lncRNA 富含功能元件，包括 RNA 结合蛋白和转录因子的结合位点，特别是核因子 kappa B（NFκB）。通过 CRISPR 筛选，我们发现与衰老相关的 13 个 lncRNA 是 NFκB 通路的调节剂，我们将这个家族命名为“NFκB 调节衰老相关 lncRNA（NFKBMARLs）”。对 NFKBMARL-1 的进一步表征表明，它可以追溯到 2900 万年前人类出现之前，并且在衰老、炎症和衰老过程中由 NFκB 诱导。反过来，NFKBMARL-1 通过与 NFKBIZ 增强子结合并将 RELA 募集到 NFKBIZ 启动子，在顺式直接调节 NFκB 抑制剂 NFKBIZ 的转录，该增强子位于同一拓扑关联域内。这些发现揭示了许多与衰老相关的 lncRNA 是 NFκB 通路中进化保守的组成部分。
