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

Abstract

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 mouse lncRNAs induced by inflammatory signaling via TNFα. TNFα 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-κB-dependent manner. Lethe, a pseudogene lncRNA, is selectively induced by proinflammatory cytokines via NF-κB or glucocorticoid receptor agonist, and functions in negative feedback signaling to NF-κB. Lethe interacts with NF-κB subunit RelA to inhibit RelA DNA binding and target gene activation. Lethe level decreases with organismal age, a physiological state associated with increased NF-κB activity. These findings suggest that expression of pseudogenes lncRNAs are actively regulated and constitute functional regulators of inflammatory signaling.

DOI: http://dx.doi.org/10.7554/eLife.00762.001

eLife digest

The simplest account of gene expression is that DNA is transcribed into messenger RNA, which is then translated into a protein. However, not all genes encode proteins; for some it is the RNA molecule itself that is the end product. Many of these ‘non-coding RNAs’ are thought to be involved in regulating the expression of other genes, but their exact functions are unknown.

Pseudogenes are genes that have lost their protein-coding abilities as a result of mutations they have accumulated mutations over the course of evolution. They were previously referred to as ‘junk DNA’ or ‘dead genes’ because they were thought to be completely non-functional, lacking even the ability to encode RNA. However, recent work has shown that pseudogenes are in fact transcribed into long non-coding RNAs, and these are now the focus of much research.

Here, Rapicavoli et al. report that certain pseudogenes and long non-coding RNAs are involved in regulating the immune response. Specific and distinct pseudogene-derived long RNAs are made when cells are exposed to different kinds of infections. Immune cells such as macrophages and lymphocytes produce a protein called tumor necrosis factor alpha (TNFα), which is involved in triggering fever and inflammation. TNFα exerts these effects by binding to and activating a transcription factor called NF-κB, which then moves to the nucleus and binds to DNA, regulating the expression of genes that encode immune proteins.

Rapicavoli et al. found that the production of a long non-coding RNA called Lethe (after the ‘river of forgetfulness’ in Greek mythology) increases when TNFα activates NF-κB. Surprisingly, however, Lethe then binds to NF-κB and prevents it from interacting with DNA, thereby reducing the production of various inflammatory proteins.

This is the first time that a pseudogene has been shown to have an active role in regulating signaling pathways involved in inflammation, and raises the possibility that other pseudogenes may also influence distinct feedback loops and signaling networks. It suggests that many novel functions for pseudogenes and long non-coding RNAs remain to be discovered.

DOI: http://dx.doi.org/10.7554/eLife.00762.002