Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-κB pathway

Abstract

Antisense Noncoding RNA in the INK4 Locus (ANRIL) is the prime candidate gene at Chr9p21, the welldefined genetic risk locus associated with multiple human diseases including coronary artery disease (CAD), while little is known regarding its role in the pathological processes. Endothelial dysfunction triggers atherosclerotic processes that are causatively linked to CAD. To evaluate the function of ANRIL in human endothelial cells (ECs), we examined ANRIL expression under pathological stimuli and found ANRIL was markedly induced by pro-inflammatory factors. Loss-of-function and chromatin immunoprecipitation approaches revealed that NF-kB mediates TNF-a induced ANRIL expression. RNA sequencing revealed that ANRIL silencing dysregulated expression of inflammatory genes including IL6 and IL8 under TNF-a treatment. We explored the regulatory mechanism of ANRIL on IL6/8 and found that Yin Yang 1 (YY1), an ANRIL binding transcriptional factor revealed by RNA immunoprecipitation, was required for IL6/8 expression under TNF-a treatment. YY1 was enriched at promoter loci of IL6/8 and ANRIL silencing impaired the enrichment, indicating a cooperation between ANRIL and YY1 in the regulation of inflammatory genes. For the first time, we establish the connection between ANRIL and NF-kB pathway and show that ANRIL regulates inflammatory responses through binding with YY1. The newly identified TNF-a-NF-kB-ANRIL/YY1-IL6/8 pathway enhances understanding of the etiology of CAD and provides potential therapeutic target for treatment of CAD.

The interplay of LncRNA ANRIL and miR‐181b on the inflammation‐relevant coronary artery disease through mediating NF‐κB signalling pathway

“…For instance, vascular endothelial cells (ECs) could perceive the pathological stimulus within blood by secreting inflammatory factors, and thereby triggering atherosclerosis. Zhou et al34 firstly disclosed that ANRIL and related inflammatory factors were up‐regulated within ECs under the stimulation of pathogens, which was mediated by up‐regulated TNF‐α that was caused by NF‐κB signalling. Also ANRIL was capable of binding to PRC‐associated protein (ie, Yin Yang 1) to induce or restrain genetic expressions (eg, IL6 and IL8) that were related with inflammatory responses 35, 36, 37.…”

Overexpression of lncRNA ANRIL up-regulates VEGF expression and promotes angiogenesis of diabetes mellitus combined with cerebral infarction by activating NF-κB signaling pathway in a rat model

“…ANRIL is a 3.8 kb lncRNA, reversing from a gene cluster named INK4B-ARF-INK4A in the direction, besides, ANRIL knockdown was found that can inhibit proliferation either in vivo or vitro [10]. A previous study demonstrated that ANRIL influences nuclear factor-κB (NF-κB) pathway in which increased ANRIL might regulate the NF-κB expressions [11]. ANRIL is supposed to be essential in mediating Chr9p21 associations and for treating a number of human diseases as a target molecule, in particular, regulating ANRIL expressions was found to be related to risk variants of DM [12].…”

Interfering with long chain noncoding RNA ANRIL expression reduces heart failure in rats with diabetes by inhibiting myocardial oxidative stress

“…A wide range of chemokines, cytokines, as well as growth factors are generated in various stages of the process, which thereby triggers pathological inflammation events during CAD pathogenesis . A recent study offered the clinical evidence that ANRIL expression level had a close association with IL‐6/IL‐8 levels in the blood, which suggested the pathological role of ANRIL related to cardiovascular disease etiology . Some inflammatory cytokines could be secreted locally from the heart, which would further elevate leukocyte activation in the injured myocardium .…”