Long non-coding RNA SeT and miR-155 regulate the Tnfα gene allelic expression profile

Abstract

It is becoming increasingly appreciated that the non-coding genome may have a great impact on the regulation of chromatin structure and gene expression. The innate immune response can be mediated upon lipopolysaccharide stimulation of macrophages which leads to immediate transcriptional activation of early responsive genes including tumor necrosis factor alpha (Tnfα). The functional role of non-coding RNAs, such as lncRNAs and microRNAs, on the transcriptional activation of proinflammatory genes and the subsequent regulation of the innate immune response is still lacking mechanistic insights. In this study we wanted to unravel the functional role of the lncRNA SeT, which is encoded from the murine Tnfα gene locus, and miR-155 on the transcriptional regulation of the Tnfα gene. We utilized genetically modified mice harboring either a deletion of the SeT promoter elements or the mature miR-155 and studied the response of macrophages to lipopolysaccharide (LPS) stimulation. We found that decreased expression of the lncRNA SeT in murine primary macrophages resulted in increased mortality of mice challenged with LPS, which was corroborated by increased Tnfα steady state mRNA levels and a higher frequency of biallelically expressing macrophages. On the contrary, miR-155 deletion resulted in reduced Tnfα mRNA levels supported by a lower frequency of biallelically expressing macrophages upon stimulation with LPS. In both cases, in the absence of either lncRNA SeT or miR-155 we observed a deregulation of the Tnfα allele homologous pairing, previously shown to regulate the switch from mono- to bi-allelic gene expression. Although lncRNA SeT was not found to be a direct target of miR-155 its stability was increased upon miR-155 deletion. This study suggests a role of the non-coding genome in mediating Tnfα mRNA dosage control based on the regulation of homologous pairing of gene alleles and their subsequent biallelic expression.

Regulation of Endotoxin Tolerance and Compensatory Anti-inflammatory Response Syndrome by Non-coding RNAs

“…LincRNA-p21 is induced by LPS in fibroblasts and regulates NFκB activity in monocytes; lincRNA-p21 physically binds to RelA/p65 mRNA blocking translation of p65, resulting in inhibition of NFκB ( 94 , 97 , 98 ). Finally, the lncRNA SeT is expressed in macrophages in response to LPS and its homologous deletion results in biallelic TNFα expression and increase in TNFα levels ( 91 ). This finding suggests that lncRNA SeT suppresses expression of one of the two TNFα alleles early upon LPS stimulation ( 91 ).…”

Long non‐coding RNA expressed in macrophage co‐varies with the inflammatory phenotype during macrophage development and polarization

“…Similarly, lincRNA THRIL as a negative regulation of NF‐κB could interact with hnRNPL at the Tnfα gene and ensure the expression of TNF‐α in dosage control, but it down‐regulated in human macrophages after TLR2 activation . Encoded by the Tnfα loci, lncRNA SeT increased in LPS‐treated murine macrophage, with unstable Tnfα mRNA . The above lncRNAs are important to reduce TNFα expression in macrophages.…”

“…74,75 Encoded by the Tnfα loci, lncRNA SeT increased in LPS-treated murine macrophage, 76 with unstable Tnfα mRNA. 20 The above lncRNAs are important to reduce TNFα expression in macrophages. NKILA was highly expressed to restrain the NF-ĸB-driven inflammation in response to TNF-α irritant.…”

“…LncRNAs are ncRNAs with critical biological roles and a length of more than 200 nucleotides . The mechanisms of lncRNAs remain unclear, but increasing number of in vitro and in vivo studies have shown that lncRNAs can be expressed in macrophage during its development and control some gene expression . However, a systematic review uncovered the interactions among lncRNAs expressed in macrophage is not available.…”

“…[15][16][17] The mechanisms of lncRNAs remain unclear, 18 but increasing number of in vitro and in vivo studies have shown that ln-cRNAs can be expressed in macrophage during its development and control some gene expression. [19][20][21] However, a systematic review uncovered the interactions among lncRNAs expressed in macrophage is not available. Hence, we reviewed recent advances in elucidation of the variability of lncRNA function within macrophages, and mainly focused on the following four aspects: biology of lncRNAs, involvement of lncRNAs in human monocyte/macrophage differentiation, characteristics of lncRNAs in macrophage polarization and dysregulation of lncRNAs in macrophage involved inflammatory diseases.…”