Aging-associated lncRNAs carry evolutionary constraints and participate in NFκB signaling [RNA]

Aging changes global transcriptome including protein-coding and noncoding RNAs. Whether aging dependent lncRNAs undergo conserved regulation and function still remain unknown. We report aging dependent lncRNAs carry signature of evolutionary constraint and significantly enriched for targets of transcription factors and RNA binding proteins. Aging dependent lncRNAs is conservatively under NFκB pathway regulation. CRISPR screening for NFκB pathway found that aging dependent lncRNAs also extensively regulate NFκB pathway. The human NFKBMARL-1 is an evolutionary conserved lncRNA that can be traced to 29Mya before human. NFKBMARL-1 is induced during aging, inflammation and senescence through NFκB pathway. Reciprocally, NFKBMARL-1 directly regulates NFKBIZ in cis within same topological associated domain (TAD). NFKBMARL-1 binds to enhancer of NFKBIZ and recruits RELA to the NFKBIZ promoters and participates phase separation. These findings reveal that aging dependent lncRNAs are previously under-appreciated contributors to the evolutionary conservation and regulation of NFκB pathway.

衰老会重塑全局转录组，涵盖编码蛋白RNA（protein-coding RNA）与非编码RNA（noncoding RNA）。衰老相关长链非编码RNA（long noncoding RNA, lncRNA）是否存在保守调控模式与功能，目前仍未明确。本研究发现，衰老相关长链非编码RNA具有进化约束特征，且显著富集于转录因子（transcription factor）与RNA结合蛋白（RNA binding protein）的靶标集合中。衰老相关长链非编码RNA保守地处于NFκB通路（NFκB pathway）的调控之下。针对NFκB通路的CRISPR筛选（CRISPR screening）实验显示，衰老相关长链非编码RNA同样可广泛调控NFκB通路。人类NFKBMARL-1是一种进化保守的长链非编码RNA，其起源可追溯至人类出现前的2900万年前（29 Mya）。NFKBMARL-1可在衰老、炎症与细胞衰老过程中通过NFκB通路被诱导表达。反之，NFKBMARL-1可在同一拓扑关联结构域（topological associated domain, TAD）内通过顺式作用直接调控NFKBIZ基因。NFKBMARL-1可结合NFKBIZ基因的增强子，并将RELA招募至NFKBIZ的启动子区域，同时参与相分离（phase separation）过程。本研究结果揭示，衰老相关长链非编码RNA是此前未被充分认知的NFκB通路进化保守性与调控机制的重要贡献者。