LincRNA-Cox2 Promotes Late Inflammatory Gene Transcription in Macrophages through Modulating SWI/SNF-Mediated Chromatin Remodeling

Abstract

LincRNAs are long non-coding transcripts (>200 nt) from the intergenic regions of annotated protein-coding genes. One of the most highly induced lincRNAs in macrophages upon TLR ligation is lincRNA-Cox2, which has recently been shown to mediate both the activation and repression of distinct classes of immune genes in innate immune cells. We report here that lincRNA-Cox2 located at chromosome 1 proximal to the prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox2) gene is an early-primary inflammatory gene controlled by NF-κB signaling in murine macrophages. Functionally, lincRNA-Cox2 is required for the transcription of NF-κB-regulated late-primary inflammatory response genes stimulated by bacterial lipopolysaccharide. Specifically, lincRNA-Cox2 is assembled into the SWI/SNF (SWItch/Sucrose NonFermentable) complex in cells after lipopolysaccharide stimulation. This resulting lincRNA-Cox2/SWI/SNF complex can modulate the assembly of NF-κB subunits to the SWI/SNF complex, and ultimately, SWI/SNF-associated chromatin remodeling and transactivation of the late-primary inflammatory response genes in macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role of NF-κB-induced lincRNA-Cox2 to act as a co-activator of NF-κB for the transcription of late-primary response genes in innate immune cells through modulation of epigenetic chromatin remodeling.

The NF-κB–Responsive Long Noncoding RNA FIRRE Regulates Posttranscriptional Regulation of Inflammatory Gene Expression through Interacting with hnRNPU

“…NF-kB signaling can regulate both the activation and inhibition of lncRNA expression (46,47). It was first described in 2013 in mouse bone marrow-derived dendritic cells that transcription of lncRNA genes in response to TLR signaling is activated in an NF-kB-dependent manner (26).…”

Long non-coding RNAs (lncRNAs) and their transcriptional control of inflammatory responses

“…Arguably the best studied lncRNA that functions to modulate the inflammatory response is lincRNA-Cox2, which has been found to act as both an enhancer and a suppressor of inflammation in a gene-specific manner (18,22,26,57). After TLR4 activation and ensuing NF-B signaling, lincRNA-Cox2 was induced greater than 1000-fold in bone marrow-derived dendritic cells over the course of the following 12 h (22).…”

“…Analysis of the expression time course revealed that it is an early primary NF-B response gene, similar to Cxcl2 (18, 57). Func-tionally, silencing of lincRNA-Cox2 resulted in up-regulation of almost 800 genes and down-regulation of many other genes in non-stimulated cells (22,57), suggesting a role for lincRNACox2 in basal gene transcription. Many of these genes are inflammatory genes, including Ccl5, Cx3cl1, Ccrl, and IFNstimulated genes, including Irf7, Oas1a, Oas1l, Oas2, Ifi204, and Isg15.…”

“…Likewise, about 700 genes were found to be downregulated, including Tlr1, Il6, and Il23␣. Mechanistically, it appears that induction of lincRNA-Cox2 does not affect the NF-B signaling cascades or RNA degradation machinery (57). Instead, lincRNA-Cox2 has been found to form a complex with heterogeneous ribonucleoprotein (hnRNP) A/B and hnRNP-A2/B1, which together function to modulate the transcription of immune response genes (22,26).…”

The Modeling and Analysis of Mechanisms for lncRNA Regulation

“…The study found that knocking out Pnky from stem cells can increase the output of neurons by three to four times, which implies that Pnky and other lncRNA will eventually play an important role in regenerative medicine and cancer treatment. More studies have focused on the lncRNA regulation of gene transcription [17,18], recent studies have shown that a new mechanism of lncRNA-Cox2 can regulate Il12B transcription, supporting lncRNA to play an important role in regulating the inflammatory response of intestinal epithelial cells [17], and lncRNA-Cox2 can mediate the activation and inhibition of different immune genes in innate immune cells [18]. In a word, the regulation of long noncoding RNA is being paid more and more attention.…”