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

Authors Shenoda BB, Tian Y, Alexander GM, Aradillas-Lopez E, Schwartzman RJ, Ajit SK

Received 12 December 2017

Accepted for publication 2 March 2018

Published 8 May 2018 Volume 2018:11 Pages 935—945

DOI https://doi.org/10.2147/JPR.S159458

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Katherine Hanlon


Botros B Shenoda,1 Yuzhen Tian,1 Guillermo M Alexander,2 Enrique Aradillas-Lopez,2,3 Robert J Schwartzman,2 Seena K Ajit1

1Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA; 2Neurology, Drexel University College of Medicine, Philadelphia, PA, USA; 3Vincera Institute, Philadelphia, PA, USA


Background: Evidence 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.
Methods: Our 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.
Results: Our 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 proinflammatory transcription factor Yin-Yang 1 (YY1). XIST was significantly upregulated in a subset of CRPS patients responding poorly to ketamine.
Conclusion: Since 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.

Keywords: long noncoding RNA, sex difference, miR-34a, inflammation, pain, XIST

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