Virginia Research Day 2022

Graduate Student Research Biomedical

12 EGR2 Is Critical For The Upregulation Of The Genomic Imprinting DLK1-DIO3 Mirnas In Murine Lupus-Prone B6/LPR Mice

Zhuang Wang 1 ; Bettina Heid 1 ; S. Ansar Ahmed 1 ; Rujuan Dai1 Corresponding author: wzhuang@vt.edu

1 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine

signaling pathway, PI3K/Akt/mTOR signaling pathway, and Foxo signaling pathway. These data suggest a critical role of the upregulated DLK1-DIO3 miRNAs in lupus. In addition to lupus, the dysregulation of DLK1-DIO3 miRNAs has been documented in various human disorders, including multiple types of cancer, type 2 diabetes mellitus, and multiple sclerosis. However, the mechanism underlying the dysregulation of DLK1-DIO3 miRNAs in these diseases, especially in lupus, remains largely unknown. Early growth response 2 (EGR2) is a transcription factor playing a critical role in regulating T cell anergy, adaptive immune response, and autoimmunity. We recently reported that EGR2 expression was significantly increased in human and murine lupus cells. Our current studies with conditional EGR2 knockout B6/lpr (EGR2 -/- B6/lpr) revealed that EGR2 played a differential immune regulatory role in non-autoimmune B6 and autoimmune-prone

B6/lpr mice. Intriguingly, we found that the in vivo deletion of EGR2 significantly reduced DLK1-DIO3 miRNAs expression in splenocytes and purified CD4 + T cells from B6/lpr. These data are the first finding of the role of EGR2 in the regulation of genomic imprinting DLK1- DIO3 miRNAs. Most recent reports have shown that EGR2 and its family members can recruit ten-eleven translocation 2 (TET2) protein to demethylate DNA and regulate gene expression epigenetically. Altogether, these data suggest a correlation among the upregulated EGR2, DNA hypomethylation, and increased DLK1- DIO3 miRNAs expression in lupus CD4 + T cells. Further studies are warranted to understand how EGR2 epigenetically regulates DLK1-DIO3 miRNAs in lupus, which will likely provide novel insights into the interplay of different genetic and epigenetic factors in lupus pathogenesis.

Over the past decades, in addition to genetic and environmental factors, epigenetic factors like DNA methylation and small non- coding microRNA (miRNA) have emerged as key contributors to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. Genomic imprinting is an epigenetic process that causes genes to be expressed or repressed based on their parental origin. Our previous reports have demonstrated that a large set of miRNAs located at the genomic imprinted DLK1- DIO3 locus were highly upregulated in three lupus-prone mouse models (MRL/lpr, B6/lpr, and NZB/W F1 ), which was correlated with the global DNA hypomethylation in lupus cells. By performing Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis with the predicted target genes of selected DLK1-DIO3 miRNAs, we found that lupus- related DLK1-DIO3 miRNAs were predicted to regulate multiple signaling cascades involved in autoimmunity such as T cell receptor

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