在研項(xiàng)目

（通訊員：朱碩）近日，華中農(nóng)業(yè)大學(xué)動(dòng)物科學(xué)技術(shù)與動(dòng)物醫(yī)學(xué)院曹勝波教授、葉靜教授團(tuán)隊(duì)在Journal of Neuroinflammation雜志上發(fā)表了題為“H3K27me3 of Rnf19a promotes neuroinflammatory response during Japanese encephalitis virus infection”的研究論文。該研究首次發(fā)現(xiàn)了表觀遺傳修飾在日本腦炎病毒誘導(dǎo)的神經(jīng)炎癥中發(fā)揮重要作用，闡明了Rnf19a調(diào)控日本腦炎病毒誘導(dǎo)神經(jīng)炎癥反應(yīng)的分子機(jī)制，為尋找日本腦炎治療藥物靶點(diǎn)提供新的線索。

日本腦炎是由日本腦炎病毒（Japanese encephalitis virus infection, JEV）感染引起的蚊媒傳播人畜共患傳染病，該病主要引起種豬的繁殖障礙，導(dǎo)致母豬流產(chǎn)，公豬睪丸炎，對(duì)我國(guó)養(yǎng)殖業(yè)造成巨大經(jīng)濟(jì)損失。同時(shí)JEV還可由豬經(jīng)蚊向人傳播，引起人神經(jīng)系統(tǒng)疾病，嚴(yán)重可造成致死性腦炎，但該病毒引起中樞神經(jīng)系統(tǒng)炎癥反應(yīng)的分子機(jī)制仍有待闡明。

研究人員首先發(fā)現(xiàn)JEV感染會(huì)導(dǎo)致小鼠小膠質(zhì)細(xì)胞系BV2、原代膠質(zhì)細(xì)胞和小鼠腦組織中H3K27me3水平明顯上調(diào)，并利用甲基化轉(zhuǎn)移酶EZH2抑制劑證明H3K27me3修飾可能在JEV誘導(dǎo)的小膠質(zhì)細(xì)胞炎癥中發(fā)揮重要的調(diào)控作用。

圖1. JEV感染引起小鼠小膠質(zhì)細(xì)胞系BV2、原代膠質(zhì)細(xì)胞和小鼠腦組織中H3K27me3水平上調(diào)

隨后，研究人員利用ChIP-Sequencing分析JEV感染細(xì)胞中H3K27me3所參與調(diào)控的基因，最終篩選出JEV感染后炎癥抑制性基因Rnf19a啟動(dòng)子區(qū)域?qū)?yīng)的H3K27me3修飾明顯上調(diào)，而Rnf19a表達(dá)量明顯下降。隨后通過使用基因敲除和過表達(dá)手段，證明了Rnf19a在JEV誘導(dǎo)的小膠質(zhì)細(xì)胞炎癥反應(yīng)中起負(fù)調(diào)控作用。進(jìn)一步實(shí)驗(yàn)證明E3泛素連接酶Rnf19a是通過泛素化降解RIG-I從而抑制炎癥反應(yīng)。以上研究結(jié)果表明JEV可通過上調(diào)Rnf19a啟動(dòng)子區(qū)域H3K27me3修飾，抑制該基因表達(dá)，從而促進(jìn)炎癥反應(yīng)的發(fā)生。

圖2.ChIP-Sequencing分析JEV感染細(xì)胞中H3K27me3參與調(diào)控的基因

我校動(dòng)科動(dòng)醫(yī)學(xué)院研究生朱碩和陶夢(mèng)穎為論文共同第一作者，葉靜教授為論文通訊作者。該研究得到國(guó)家自然科學(xué)基金、國(guó)家重點(diǎn)研發(fā)計(jì)劃項(xiàng)目等項(xiàng)目資助。

【英文摘要】

Histone methylation is an important epigenetic modification that affects various biological processes, including the inflammatory response. In this study, we found that infection with Japanese encephalitis virus (JEV) leads to an increase in H3K27me3 in BV2 microglial cell line, primary mouse microglia and mouse brain. Inhibition of H3K27me3 modification through EZH2 knockdown and treatment with EZH2 inhibitor significantly reduces the production of pro-inflammatory cytokines during JEV infection, which suggests that H3K27me3 modification plays a crucial role in the neuroinflammatory response caused by JEV infection.The chromatin immunoprecipitation-sequencing (ChIP-sequencing) assay revealed an increase in H3K27me3 modification of E3 ubiquitin ligases Rnf19a following JEV infection, which leads to downregulation of Rnf19a expression. Furthermore, the results showed that Rnf19a negatively regulates the neuroinflammatory response induced by JEV. This is achieved through the degradation of RIG-I by mediating its ubiquitination. In conclusion, our findings reveal a novel mechanism by which JEV triggers extensive neuroinflammation from an epigenetic perspective.

原文連接：https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02852-4

審核人：葉靜