YY1 regulation by miR-124-3p promotes Th17 cell pathogenicity through interaction with T-bet in rheumatoid arthritis
Jinpiao Lin, Jifeng Tang, Junyu Lin, Yujue He, Ziqing Yu, Renquan Jiang, Bin Yang, Qishui Ou
Jinpiao Lin, Jifeng Tang, Junyu Lin, Yujue He, Ziqing Yu, Renquan Jiang, Bin Yang, Qishui Ou
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Research Article Immunology

YY1 regulation by miR-124-3p promotes Th17 cell pathogenicity through interaction with T-bet in rheumatoid arthritis

Abstract

Th17 cells are involved in rheumatoid arthritis (RA) pathogenesis. Our previous studies have revealed that transcription factor Yin Yang 1 (YY1) plays an important role in the pathogenic mechanisms of RA. However, whether YY1 has any role in Th17 cell pathogenicity and what molecular regulatory mechanism is involved remain poorly understood. Here, we found the proportion of pathogenic Th17 (pTh17) cells was significantly higher in RA than in control individuals and showed a potential relationship with YY1 expression. In addition, we also observed YY1 expression was increased in pTh17, and the pTh17 differentiation was hampered by YY1 knockdown. Consistently, knockdown of YY1 decreased the proportion of pTh17 cells and attenuated joint inflammation in collagen-induced arthritis mice. Mechanistically, YY1 could regulate the pathogenicity of Th17 cells through binding to the promoter region of transcription factor T-bet and interacting with T-bet protein. This function of YY1 for promoting pTh17 differentiation was specific to Th17 cells and not to Th1 cells. Moreover, we found miR-124-3p negatively correlated with YY1 in RA patients, and it could bind to 3′-UTR regions of YY1 to inhibit the posttranscriptional translation of YY1. Altogether, these findings indicate YY1 regulation by miR-124-3p could specifically promote Th17 cell pathogenicity in part through interaction with T-bet, and these findings present promising therapeutic targets in RA.

Authors

Jinpiao Lin, Jifeng Tang, Junyu Lin, Yujue He, Ziqing Yu, Renquan Jiang, Bin Yang, Qishui Ou

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Figure 6

miR-124-3p targets the 3′-UTR of YY1 mRNA.

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miR-124-3p targets the 3′-UTR of YY1 mRNA. (A) Diagrams of predicted miR...
(A) Diagrams of predicted miRNA target sites in the 3′-UTR of YY1. The solid lines represent miRNA-mRNA interactions as predicted by TargetScan. (B) Luciferase activity of HEK293T cells cotransfected with the pmirGLO vectors fused to the 3′-UTR of YY1 mRNA and predicted miRNAs mimics, inhibitors, or respective control plasmid. Data presented as mean ± SEM (n = 3 independent experiments). **P < 0.01, *P < 0.05 (Student’s t test). (C) Luciferase activity of HEK293T cells cotransfected with miR-124-3p mimics, inhibitors or respective control plasmid together with the vectors containing mutant or wild-type binding sites of miR-124-3p in YY1 3′-UTR. Data presented as mean ± SEM (n = 3 independent experiments). *P < 0.05, ***P < 0.001 (Student’s t test). (D) Representative Western blots of YY1 in HEK293T cells transfected with miRNAs mimics, inhibitors, or respective control plasmid and (E) the grayscale analysis of Western blot analysis results. Data presented as mean ± SEM (n = 3 independent experiments). *P < 0.05 (Student’s t test). (F) The relative gene expression levels of miRNAs and YY1 in purified CD4+ T cells of patients with RA (n = 36) and HD (n = 18). Data presented as mean ± SD. ***P < 0.001, *P < 0.05 (Student’s t test). (G) Analysis of the correlation of YY1 mRNA and miR-124-3p in purified CD4+ T cells of RA patients (n = 36, Pearson correlation).