Wang, ZuhangHeid, BettinaHe, JianlinXie, HehuangReilly, Christopher M.Dai, RujuanAhmed, S. Ansar2025-05-122025-05-122023-122573-7732266574 (PII)https://hdl.handle.net/10919/131425We 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.Pages 898-907application/pdfenCreative Commons Attribution 4.0 InternationalAnimalsMice, Inbred C57BLMice, Inbred MRL lprMiceCalcium-Binding ProteinsMicroRNAsDNAAutoimmunityDNA MethylationEarly Growth Response Protein 2Article - Refereedhttps://doi.org/10.4049/immunohorizons.2300111712Dai, Rujuan [0000-0002-1074-8974]Xie, Hehuang [0000-0001-5739-1653]381533512573-7732