Egr2 Deletion in Autoimmune-Prone C57BL6/lpr Mice Suppresses the Expression of Methylation-Sensitive Dlk1-Dio3 Cluster MicroRNAs.

Q3 Medicine ImmunoHorizons Pub Date : 2023-12-01 DOI:10.4049/immunohorizons.2300111
Zhuang Wang, Bettina Heid, Jianlin He, Hehuang Xie, Christopher M Reilly, Rujuan Dai, S Ansar Ahmed
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Abstract

We previously demonstrated that the upregulation of microRNAs (miRNAs) at the genomic imprinted Dlk1-Dio3 locus in murine lupus is correlated with global DNA hypomethylation. We now report that the Dlk1-Dio3 genomic region in CD4+ T cells of MRL/lpr mice is hypomethylated, linking it to increased Dlk1-Dio3 miRNA expression. We evaluated the gene expression of methylating enzymes, DNA methyltransferases (DNMTs), and demethylating ten-eleven translocation proteins (TETs) to elucidate the molecular basis of DNA hypomethylation in lupus CD4+ T cells. There was a significantly elevated expression of Dnmt1 and Dnmt3b, as well as Tet1 and Tet2, in CD4+ T cells of three different lupus-prone mouse strains compared to controls. These findings suggest that the hypomethylation of murine lupus CD4+ T cells is likely attributed to a TET-mediated active demethylation pathway. Moreover, we found that deletion of early growth response 2 (Egr2), a transcription factor gene in B6/lpr mice markedly reduced maternally expressed miRNA genes but not paternally expressed protein-coding genes at the Dlk1-Dio3 locus in CD4+ T cells. EGR2 has been shown to induce DNA demethylation by recruiting TETs. Surprisingly, we found that deleting Egr2 in B6/lpr mice induced more hypomethylated differentially methylated regions at either the whole-genome level or the Dlk1-Dio3 locus in CD4+ T cells. Although the role of methylation in EGR2-mediated regulation of Dlk1-Dio3 miRNAs is not readily apparent, these are the first data to show that in lupus, Egr2 regulates Dlk1-Dio3 miRNAs, which target major signaling pathways in autoimmunity. These data provide a new perspective on the role of upregulated EGR2 in lupus pathogenesis.

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自身免疫易感性 C57BL6/lpr 小鼠的 Egr2 基因缺失抑制甲基化敏感的 Dlk1-Dio3 簇 MicroRNAs 的表达
我们以前曾证实,小鼠狼疮基因组印迹 Dlk1-Dio3 基因座上微小 RNA(miRNA)的上调与全局 DNA 低甲基化有关。我们现在报告说,MRL/lpr 小鼠 CD4+ T 细胞中的 Dlk1-Dio3 基因组区域发生了低甲基化,这与 Dlk1-Dio3 miRNA 表达的增加有关。我们评估了甲基化酶、DNA 甲基转移酶(DNMTs)和去甲基化十-十一转位蛋白(TETs)的基因表达,以阐明狼疮 CD4+ T 细胞 DNA 低甲基化的分子基础。与对照组相比,三种不同狼疮易感小鼠品系的CD4+ T细胞中Dnmt1和Dnmt3b以及Tet1和Tet2的表达明显升高。这些发现表明,小鼠狼疮 CD4+ T 细胞的低甲基化很可能是由 TET 介导的活性去甲基化途径造成的。此外,我们还发现,在 B6/lpr 小鼠中,早期生长应答 2(Egr2)转录因子基因的缺失明显减少了 CD4+ T 细胞 Dlk1-Dio3 基因座上母系表达的 miRNA 基因,但没有减少父系表达的蛋白编码基因。EGR2 已被证明能通过招募 TETs 诱导 DNA 去甲基化。令人惊讶的是,我们发现在 B6/lpr 小鼠中删除 Egr2 会诱导 CD4+ T 细胞中全基因组水平或 Dlk1-Dio3 基因座上更多的低甲基化差异甲基化区域。尽管甲基化在 EGR2 介导的 Dlk1-Dio3 miRNA 调控中的作用并不明显,但这些数据首次表明,在狼疮中,Egr2 可调控 Dlk1-Dio3 miRNA,而 Dlk1-Dio3 miRNA 是自身免疫中主要信号通路的靶标。这些数据为研究 EGR2 上调在狼疮发病机制中的作用提供了新的视角。
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