miR-34a-mediated regulation of XIST in female cells under inflammation

Abstract

BackgroundEvidence is overwhelming for sex differences in pain, with women representing the majority of the chronic pain patient population. There is a need to explore novel avenues to elucidate this sex bias in the development of chronic inflammatory pain conditions. Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder, and the incidence of CRPS is greater in women than in men by ~4:1. Since neurogenic inflammation is a key feature of CRPS, dysregulation of inflammatory responses can be a factor in predisposing women to chronic pain.MethodsOur studies investigating alterations in circulating microRNAs (miRNAs) in whole blood from female CRPS patients showed significant differential expression of miRNAs between responders and poor responders to ketamine treatment. Several of these miRNAs are predicted to target the long noncoding RNA, X-inactive-specific transcript (XIST). XIST mediates X-chromosome inactivation and is essential for equalizing the expression of X-linked genes between females and males. Based on the well-established role in inflammatory process, we focused on miR-34a, one of the miRNAs predicted to target XIST, and downregulated in CRPS patients responding poorly to ketamine.ResultsOur in vitro and in vivo models of acute inflammation and data from patients with CRPS showed that miR-34a can regulate XIST under inflammation directly, and through pro-inflammatory transcription factor Yin-Yang 1 (YY1). XIST was significantly upregulated in a subset of CRPS patients responding poorly to ketamine.ConclusionSince dysregulation of XIST can result in genes escaping inactivation or reactivation in female cells, further investigations on the role of XIST in the predominance of chronic inflammatory and pain disorders in women is warranted.

Knockdown XIST alleviates LPS‐induced WI‐38 cell apoptosis and inflammation injury via targeting miR‐370‐3p/TLR4 in acute pneumonia

“…XIST was reported to promote cancer development and could cause inflammation response in chronic constriction injury, neuropathic pain, and chronic pain . To profile the expression of XIST in LPS‐injured WI‐38 cells, qRT‐RCR analysis was evaluated.…”

High susceptibility to collagen-induced arthritis in mice with progesterone receptors selectively inhibited in osteoprogenitor cells

“…We identified PR-targeted genes that regulated sex differences, including an "X-inactive specific transcript," Xist, Mtus2, Aldhla7/1, Tusc5, Cd300c, and Pde3a [34]. The upregulation of Xist is associated with chronic inflammation and pain in females with complex regional pain syndrome [73] and contributes to RA progression [74]. Cd300c and Pde3a were over-presented in RA patients [75,76] and were associated with inhibition of T cell immunity [77] or response to TNF inhibitors in RA patients [78].…”

Non-coding RNAs in neuropathic pain

“…lncRNAs are deregulated in diabetic peripheral neuropathy and CRPS [57,137,[174][175][176], and similar to miRNAs, they can be detected in liquid biopsies ( Table 4). The most studied lncRNA in DNP is NONRATT021972 which is up-regulated in the serum and correlates with higher neuropathic pain scores, indicating its potential as a biomarker [137,177].…”

“…Amongst 1327 deregulated lncRNAs in the PBMCs of female patients with DNP, MALAT1, H19, PVT1 and MIR143HG could potentially qualify as biomarkers [174]. In female CRPS patients, XIST appears as a promising indicator of poor responsiveness to ketamine [57]. XIST acts as a ceRNA on miR-34a, thus enhancing expression levels of the transcription factor YY1 promoting XIST expression in an autoregulatory loop [57].…”

“…In female CRPS patients, XIST appears as a promising indicator of poor responsiveness to ketamine [57]. XIST acts as a ceRNA on miR-34a, thus enhancing expression levels of the transcription factor YY1 promoting XIST expression in an autoregulatory loop [57]. CircRNAs are much less studied in patients with neuropathic pain and currently there is only one study showing that circHIPK3 expression positively correlates with the severity of neuropathic pain in diabetic patients [176].…”