中國科學(xué)院上海生命科學(xué)研究院健康科學(xué)研究所沈南教授領(lǐng)導(dǎo)的研究組整合上海交通大學(xué)附屬仁濟(jì)醫(yī)院風(fēng)濕科的臨床優(yōu)勢和健康所的基礎(chǔ)研究力量,，繼2009年在風(fēng)濕病學(xué)領(lǐng)域最有影響力的雜志ARTHRITIS & RHEUMATISM上報(bào)道了miRNA作為負(fù)反饋調(diào)節(jié)分子在狼瘡關(guān)鍵致病通路中起了重要作用后，近日又在國際學(xué)術(shù)期刊Journal of immunology發(fā)表了有關(guān)miRNA參與狼瘡T細(xì)胞低甲基化調(diào)控的最新研究成果,。該工作揭示了miRNA參與狼瘡發(fā)病的新機(jī)制,，為今后發(fā)展miRNA為靶點(diǎn)的干預(yù)治療提供了重要依據(jù)。
系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus, SLE) 發(fā)病機(jī)理復(fù)雜,，被認(rèn)為是自身免疫病的原型,，T淋巴細(xì)胞異常低甲基化在SLE的發(fā)病中起著重要作用。但狼瘡T細(xì)胞異常低甲基化的機(jī)制尚未闡明,。MicroRNA(miRNA)是近年來廣為關(guān)注的重要的基因表達(dá)調(diào)控因子,，SLE患者T細(xì)胞異常低甲基化可能與某些miRNA異常表達(dá)有關(guān)。
為探索這一關(guān)鍵問題,，研究人員通過高通量和特異性的miRNA表達(dá)譜分析,、篩選發(fā)現(xiàn)，miR-21和miR-148a在SLE小鼠模型T淋巴細(xì)胞異常高表達(dá),。探索miR-21和miR-148a的表達(dá)與疾病臨床表型的相關(guān)性,，發(fā)現(xiàn)在SLE患者T細(xì)胞中這兩個(gè)miRNA的表達(dá)水平與疾病的活動性以及免疫相關(guān)的甲基化敏感基因的表達(dá)呈正相關(guān)。進(jìn)一步機(jī)制研究發(fā)現(xiàn),，狼瘡T細(xì)胞中高表達(dá)的miR-21通過直接抑制DNMT1上游信號分子RASGRP1而間接調(diào)控DNMT1的表達(dá),，miR-148a通過直接靶向DNMT1的編碼區(qū)來調(diào)控DNMT1的表達(dá)，加速細(xì)胞內(nèi)低甲基化狀態(tài),，誘導(dǎo)自身免疫相關(guān)的甲基化敏感基因啟動子區(qū)域去甲基化,，上調(diào)敏感基因的表達(dá)，介導(dǎo)疾病發(fā)生,。使用這兩個(gè)miRNA特異性抑制劑對SLE病人T淋巴細(xì)胞進(jìn)行干預(yù)處理,，發(fā)現(xiàn)能夠有效逆轉(zhuǎn)低甲基化狀態(tài)。
該項(xiàng)研究表明,，miR-21和miR-148a有望成為調(diào)控SLE患者T淋巴細(xì)胞異常低甲基化的新靶點(diǎn),，改變SLE患者T淋巴細(xì)胞內(nèi)的miR-21和miR-148a表達(dá)水平可作為潛在的干預(yù)治療手段,。
該項(xiàng)工作得到國家科技部、國家自然科學(xué)基金和上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
RNAi-miRNA專題
Nature：miRNA和根細(xì)胞命運(yùn)
Gene&Development：MicroRNA-140 或可催生關(guān)節(jié)炎治療新
Molecular Cell：調(diào)控靶標(biāo)基因的一類新miRNAs
Nature：與基因沉默有關(guān)的特殊基因RDM1
生物谷推薦原文出處：
The Journal of Immunology, 2010, doi:10.4049/jimmunol.0904060
MicroRNA-21 and MicroRNA-148a Contribute to DNA Hypomethylation in Lupus CD4+ T Cells by Directly and Indirectly Targeting DNA Methyltransferase 1
Wen Pan,*,1 Shu Zhu,,1 Min Yuan,* Huijuan Cui,*, Lijia Wang,* Xiaobing Luo,*, Jia Li,* Haibo Zhou,*, Yuanjia Tang,*, and Nan Shen*,
*Joint Molecular Rheumatology Laboratory, Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, Laboratory of Immunity and Diseases, Institute of Health Sciences, and Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Systemic lupus erythematosus is a complex autoimmune disease caused by genetic and epigenetic alterations. DNA methylation abnormalities play an important role in systemic lupus erythematosus disease processes. MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states, including human lupus. Whereas previous studies have shown miRNAs can regulate DNA methylation by targeting the DNA methylation machinery, the role of miRNAs in aberrant CD4+ T cell DNA hypomethylation of lupus is unclear. In this study, by using high-throughput microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both patients with lupus and lupus-prone MRL/lpr mice, which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. This in turn leads to the overexpression of autoimmune-associated methylation-sensitive genes, such as CD70 and LFA-1, via promoter demethylation. Further experiments revealed that miR-21 indirectly downregulated DNMT1 expression by targeting an important autoimmune gene, RASGRP1, which mediated the Ras–MAPK pathway upstream of DNMT1; miR-148a directly downregulated DNMT1 expression by targeting the protein coding region of its transcript. Additionally, inhibition of miR-21 and miR-148a expression in CD4+ T cells from patients with lupus could increase DNMT1 expression and attenuate DNA hypomethylation. Together, our data demonstrated a critical functional link between miRNAs and the aberrant DNA hypomethylation in lupus CD4+ T cells and could help to develop new therapeutic approaches.
