Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes

Abstract

Early reports indicate that long non-coding RNAs (lncRNAs) are novel regulators of biological responses. However, their role in the human innate immune response, which provides the initial defence against infection, is largely unexplored. To address this issue, here we characterize the long non-coding RNA transcriptome in primary human monocytes using RNA sequencing. We identify 76 enhancer RNAs (eRNAs), 40 canonical lncRNAs, 65 antisense lncRNAs and 35 regions of bidirectional transcription (RBT) that are differentially expressed in response to bacterial lipopolysaccharide (LPS). Crucially, we demonstrate that knockdown of nuclear-localized, NF-κB-regulated, eRNAs (IL1β-eRNA) and RBT (IL1β-RBT46) surrounding the IL1β locus, attenuates LPS-induced messenger RNA transcription and release of the proinflammatory mediators, IL1β and CXCL8. We predict that lncRNAs can be important regulators of the human innate immune response.

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

“…LPS treatment provides the opportunity to screen for "facultative" or "signal-dependent" SEs that can be "gained" or "lost" during macrophage activation (34,36). Indeed, within minutes of LPS addition, 80 new SEs materialize, whereas 277 SEs recede within minutes of LPS addition (Fig.…”

“…It has also been strongly implicated that eRNAs and enhancer functions are involved in the regulation of inflammatory transcription networks (22,(34)(35)(36)(37); however, it remains to be solved how, and if at all, SE-associated eRNAs (seRNAs) contribute to the regulatory landscape. Using global nuclear run-on sequencing (GRO-Seq) to map the location and orientation of all active RNA polymerases genome-wide (38), we found eRNAs extensively transcribed within the macrophage SE subset.…”

p38MAPK/MK2-mediated phosphorylation of RBM7 regulates the human nuclear exosome targeting complex

“…In addition to PROMPTs, enhancer (e) RNAs are also targeted for rapid nuclear decay by the RNA exosome (Andersson et al 2014) and thus potentially regulated via RBM7 phosphorylation upon stress. Some eRNAs function as regulators of cell type-specific gene expression events (Kim et al 2010;Ilott et al 2014). Furthermore, several examples have assigned specific functions to lncRNAs during the classical stress response, e.g., the lncRNA HSR1 acts as an RNA stress sensor, which contributes to HSF1 trimerization (Shamovsky et al 2006), and the lncRNA 7SK functions as repressor of the P-TEFb complex blocking RNAPII CTD-phosphorylation and elongation of transcription (Nguyen et al 2001).…”

Acute Thymic Involution and Mechanisms for Recovery

“…Modulated expression of lncRNAs under LPS-induced stress has been identified in human monocytes, and these molecules are therefore considered to be essential regulators of the innate immune response (Ilott et al 2014). Moreover, the lncRNA NeST [nettoie Salmonella pas Theiler's (cleanup Salmonella not Theiler's)] was reported to control the IFN-γ locus in CD8 + T cells and thus decrease the vulnerability to Salmonella infection in mice after LPS treatment (Gomez et al 2013).…”