Aging-associated lncRNAs are evolutionarily conserved and participate in NFκB signaling

Abstract

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.