Deficiency of p53 Causes the Inadequate Expression of miR-1246 in B Cells of Systemic Lupus Erythematosus
Deficiency of p53 Causes the Inadequate Expression of miR-1246 in B Cells of Systemic Lupus Erythematosus
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p53缺陷导致系统性红斑狼疮B细胞中miR-1246表达不足
DOI：
10.4049/jimmunol.2200307
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发表时间：
2022-09
影响因子：
4.4
通讯作者：
Shuangyan Luo
中科院分区：
文献类型：
--
作者：
Qing Zhang;Yu Liu;Jieyue Liao;Ruifang Wu;Yi Zhan;Peng Zhang;Shuangyan Luo
p53表达下调被认为是系统性红斑狼疮（SLE）患者B细胞中miR-1246表达降低的主要原因，但确切的作用机制仍不清楚。为了进一步探讨p53上调miR-1246表达的分子机制，我们针对SLE B细胞miR-1246启动子区组蛋白H3的甲基化和乙酰化进行了研究。我们发现miR-1246启动子区Lys 27处组蛋白H3三甲基化（H3 K27 me 3）的增加和Lys 9和Lys 14处组蛋白H3乙酰化（H3 K9/K14 ac）的减少是SLE B细胞中miR-1246低表达所必需的。p53可以通过募集Jumonji结构域蛋白3（JMJD 3）、E1 A结合蛋白p300（EP 300）和CREB结合蛋白（CBP）与miR-1246启动子结合，下调H3 K27 me 3和上调H3 K9/K14 ac来促进miR-1246的转录。p53表达质粒转染的SLE B细胞中早期B细胞因子1（EBF 1）、CD 40、CD 38和X盒结合蛋白1（XBP-1）的表达水平显著降低，而与过表达p53的SLE B细胞共培养的自体CD 4 + T细胞中自身抗体IgG的产生减少。总的来说，我们的数据表明，p53的减少通过上调H3 K27 me 3和下调H3 K9/14 ac来降低miR-1246表达，这反过来导致SLE B细胞过度活跃。p53直接上调B细胞中miR-1246的表达。p53调控miR-1246启动子中的组蛋白H3 K27 me 3和H3 K9/K14 ac。p53募集JMJD 3和EP 300/CBP与miR-1246启动子结合。
Underexpression of p53 is considered the leading cause of the decreased miR-1246 expression in B cells of systemic lupus erythematosus (SLE) patients, yet the exact mechanism of action still remains unclear. To further explore the molecular mechanism of p53 upregulating miR-1246 expression, we targeted the methylation and acetylation of histone H3 in the miR-1246 promoter region of SLE B cells. We found that increased histone H3 trimethylation at Lys27 (H3K27me3) and decreased histone H3 acetylation at Lys9 and Lys14 (H3K9/K14ac) in the miR-1246 promoter region are essential for the low expression of miR-1246 in SLE B cells. p53 can promote miR-1246 transcription by recruiting Jumonji domain–containing protein 3 (JMJD3), E1A-binding protein p300 (EP300), and CREB-binding protein (CBP) to bind to the miR-1246 promoter, downregulating H3K27me3 and upregulating H3K9/K14ac. Furthermore, early B cell factor 1 (EBF1), CD40, CD38, and X box binding protein-1 (XBP-1) expression levels in SLE B cells transfected with p53 expression plasmid were significantly decreased, whereas autoantibody IgG production in autologous CD4+ T cells cocultured with overexpressed p53 SLE B cells was reduced. Collectively, our data suggest that the reduction of p53 decreases miR-1246 expression via upregulation of H3K27me3 and downregulation of H3K9/14ac, which in turn results in SLE B cell hyperactivity. Key Points p53 directly upregulates miR-1246 expression in B cells. p53 regulates histone H3K27me3 and H3K9/K14ac in the miR-1246 promoter. p53 recruits JMJD3 and EP300/CBP to bind to the miR-1246 promoter.
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影响因子：
10.5
作者：
Gyoery, Ildiko;Boller, Soeren;Grosschedl, Rudolf
通讯作者：
Grosschedl, Rudolf
DOI：
10.1073/pnas.152333199
发表时间：
2002-07-23
影响因子：
11.1
作者：
Yamanishi, Y;Boyle, DL;Firestein, GS
通讯作者：
Firestein, GS
影响因子：
64.8
作者：
Green, Douglas R.;Kroemer, Guido
通讯作者：
Kroemer, Guido
影响因子：
56.9
作者：
Cao, R;Wang, LJ;Zhang, Y
通讯作者：
Zhang, Y
造血祖细胞激酶 1 的抑制表达与含有 3 启动子结合的 jumonji 结构域丢失相关，有助于系统性红斑狼疮的自身免疫
影响因子：
12.8
作者：
Zhang, Qing;Long, Hai;Lu, Qianjin
通讯作者：
Lu, Qianjin