A pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics

Pseudogenes are thought to be inactive gene sequences, but recent evidence of extensive pseudogene transcription raised the question of potential function. Here we discover and characterize the sets of lncRNAs induced by inflammatory signaling via TNFa. TNFa regulates hundreds of lncRNAs, including 54 pseudogene lncRNAs, several of which show exquisitely selective expression in response to specific cytokines and microbial components in a NF-?B-dependent manner. Lethe, a pseudogene lncRNA, is selectively induced by proinflammatory cytokines via NF-?B or glucocorticoid receptor agonist, and functions in negative feedback signaling to NF-?B. Lethe interacts with NF-?B subunit RelA to inhibit RelA DNA binding and target gene activation. Lethe level decreases with organismal age, a physiological state associated with increased NF-?B activity. These findings suggest that expression of pseudogenes lncRNAs are actively regulated and constitute functional regulators of inflammatory signaling. Overall design: RNA profiles of wild type (WT) MEFs treated with TNF-alpha were generated by deep sequencing using Illumina GAIIx. Examination of H3K4me3 histome modification in MEF.