MicroRNA-1224 Splicing CircularRNA-Filip1l in an Ago2-Dependent Manner Regulates Chronic Inflammatory Pain via Targeting Ubr5

Pan, ZQ; Li, GF; Sun, ML; Xie, L; Liu, D; Zhang, Q; Yang, XX; Xia, SH; Liu, XD; Zhou, HM; Xue, ZY; Zhang, M; Hao, LY; Zhu, LJ; Cao, JL

Pan, ZQ; Cao, JL (reprint author), Xuzhou Med Univ, Jiangsu Prov Key Lab Anesthesiol, Xuzhou 221004, Jiangsu, Peoples R China.; Pan, ZQ; Cao, JL (reprint author), Xuzhou Med Univ, Jiangsu Prov Key Lab Anesthesia & Analgesia Appli, Xuzhou 221004, Jiangsu,

JOURNAL OF NEUROSCIENCE, 2019; 39 (11): 2125

Abstract

Dysfunctions of gene transcription and translation in the nociceptive pathways play the critical role in development and maintenance of chronic pain. Circular RNAs (circRNAs) are emerging as new players in regulation of gene expression, but whether and how circRNAs are involved in chronic pain remain elusive. We showed here that complete Freund's adjuvant-induced chronic inflammation pain significantly increased circRNA-Filipi1l (filamin A interacting protein 1-like) expression in spinal neurons of mice. Blockage of this increase attenuated complete Freund's adjuvant-induced nociceptive behaviors, and overexpression of spinal circRNA-Filipi1l in naive mice mimicked the nociceptive behaviors as evidenced by decreased thermal and mechanical nociceptive threshold. Furthermore, we found that mature circ RNA-Filipllexpression was negatively regulated by miRNA-1224 via binding and splicing of precursor of circRNA-Filipi1l (pre-circRNA-Filipi1l) in the Argonaute-2 (Ago2)-dependent manner. Increase of spinal circRNA-Filipi1l expression resulted from the decrease of m iRNA-1224 expression under chronic inflammation pain state. miRNA-1224 knockdown or Ago2 overexpression induced nociceptive behaviors in naive mice, which was prevented by the knockdown of spinal circRNA-Filipi1l. Finally, we demonstrated that a ubiquitin protein ligase E3 component n-recognin 5 (Ubr5), validated as a target of circRNA-Filipi1l, plays a pivotal role in regulation of nociception by spinal circRNA-Filipi1l. These data suggest that miRNA-1224-mediated and Ago2-dependent modulation of spinal circRNA-Filipi1l expression regulates nociception via targeting Ubr5, revealing a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.

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