RGS1 Enhancer RNA Promotes Gene Transcription by Recruiting Transcription Factor FOXJ3 and Facilitates Osteoclastogenesis Through PLC-IP3R-dependent Ca2+ Response in Rheumatoid Arthritis.

IF 4.5 2区 医学 Q2 CELL BIOLOGY
Inflammation Pub Date : 2025-02-01 Epub Date: 2024-06-21 DOI:10.1007/s10753-024-02067-6
Lin Yuan, Nan Jiang, Yuxuan Li, Xin Wang, Wei Wang
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Abstract

Recent evidence has highlighted the functions of enhancers in modulating transcriptional machinery and affecting the development of human diseases including rheumatoid arthritis (RA). Enhancer RNAs (eRNAs) are RNA molecules transcribed from active enhancer regions. This study investigates the specific function of eRNA in gene transcription and osteoclastogenesis in RA. Regulator of G protein signaling 1 (RGS1)-associated eRNA was highly activated in osteoclasts according to bioinformatics prediction. RGS1 mRNA was increased in mice with collagen-induced arthritis as well as in M-CSF/soluble RANKL-stimulated macrophages (derived from monocytes). This was ascribed to increased RGS1 eRNA activity. Silencing of 5'-eRNA blocked the binding between forkhead box J3 (FOXJ3) and the RGS1 promoter, thus suppressing RGS1 transcription. RGS1 accelerated osteoclastogenesis through PLC-IP3R-dependent Ca2+ response. Knockdown of either FOXJ3 or RGS1 ameliorated arthritis severity, improved pathological changes, and reduced osteoclastogenesis and bone erosion in vivo and in vitro. However, the effects of FOXJ3 silencing were negated by RGS1 overexpression. In conclusion, this study demonstrates that the RGS1 eRNA-driven transcriptional activation of the FOXJ3/RGS1 axis accelerates osteoclastogenesis through PLC-IP3R dependent Ca2+ response in RA. The finding may offer novel insights into the role of eRNA in gene transcription and osteoclastogenesis in RA.

Abstract Image

RGS1 Enhancer RNA 通过招募转录因子 FOXJ3 促进基因转录,并通过 PLC-IP3R 依赖性 Ca2+ 响应促进类风湿关节炎的破骨细胞生成。
最近有证据表明,增强子具有调节转录机制和影响人类疾病(包括类风湿性关节炎)发展的功能。增强子 RNA(eRNA)是从活性增强子区域转录的 RNA 分子。本研究探讨了 eRNA 在类风湿性关节炎基因转录和破骨细胞生成中的特定功能。根据生物信息学预测,G蛋白信号调节器1(RGS1)相关的eRNA在破骨细胞中被高度激活。RGS1 mRNA在胶原诱导的关节炎小鼠以及M-CSF/可溶性RANKL刺激的巨噬细胞(来源于单核细胞)中均有所增加。这归因于 RGS1 eRNA 活性的增加。5'-eRNA 的沉默阻断了叉头盒 J3(FOXJ3)与 RGS1 启动子之间的结合,从而抑制了 RGS1 的转录。RGS1 通过 PLC-IP3R 依赖性 Ca2+ 反应加速破骨细胞生成。在体内和体外敲除 FOXJ3 或 RGS1 可改善关节炎的严重程度,改善病理变化,减少破骨细胞生成和骨侵蚀。然而,沉默 FOXJ3 的效果被 RGS1 的过表达所抵消。总之,本研究表明,RGS1 eRNA 驱动的 FOXJ3/RGS1 轴转录激活通过 PLC-IP3R 依赖性 Ca2+ 反应加速了 RA 的破骨细胞生成。这一发现可能为 eRNA 在 RA 基因转录和破骨细胞生成中的作用提供了新的见解。
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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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