Abstract
Epigenetic factors such as DNA methylation and microRNAs (miRNAs) are now increasingly recognized as vital contributors to lupus etiology. In this study, we investigated the potential interaction of these two epigenetic factors in lupus-prone MRL-lpr mice. We recently reported dysregulated expression of miRNAs in splenocytes of MRL-lpr mice. Here, we report that a majority of the upregulated miRNAs in MRL-lpr mice is located at the genomic imprinted DLK1-Dio3 domain. Further, we show a differential magnitude of upregulation of DLK1-Dio3 miRNA cluster in purified splenic CD4+ T, CD19+ B, and splenic CD4-CD19- cells from MRL-lpr lupus mice when compared to control MRL mice. MRL-lpr splenocytes (especially CD19+ and CD4-CD19- subsets) were hypomethylated compared to cells from control, MRL mice. We further show that deliberate demethylation of splenocytes from control MRL mice, but not from MRL-lpr lupus mice, with specific DNA methylation inhibitor 5-Aza-2’-deoxycytidine significantly augmented DLK1-Dio3 miRNAs expression. These findings strongly indicate that the upregulation of DLK1-Dio3 miRNAs in lupus splenic cell subsets is associated with reduced global DNA methylation levels in lupus cells. There was a differential upregulation of DLK-Dio3 miRNAs among various demethylated splenic cell subsets, which implies varied sensitivity of DLK1-Dio3 miRNA cluster in these cell subsets to DNA hypomethylation. Finally, inhibition of select DLK1-Dio3 miRNA such as miR-154, miR-379 and miR-300 with specific antagomirs significantly reduced the production of lupus-relevant IFNγ, IL-1β, IL-6, and IL-10 in lipopolysaccharide (LPS) activated splenocytes from MRL-lpr mice. Our study is the first to show that DNA methylation regulates genomic imprinted DLK1-Dio3 miRNAs in autoimmune lupus, which suggests a connection of DNA methylation, miRNA and genomic imprinting in lupus pathogenesis.
Highlights
Systemic lupus erythematosus (SLE) is a female predominant autoimmune disease that is characterized by the production of autoantibodies against various nuclear antigens and multi-organ damage
This suggests the possibility of upregulation of the entire DLK1-Dio3 miRNA cluster in MRL-lpr splenocytes
Considering the cell-specific expression and function of miRNA, we further investigated the expression of aforementioned DLK1-Dio3 miRNAs in various purified splenic cell subsets
Summary
Systemic lupus erythematosus (SLE) is a female predominant autoimmune disease that is characterized by the production of autoantibodies against various nuclear antigens and multi-organ damage. It is well acknowledged that in addition to genetic factors, different epigenetic factors such as histone modification, DNA methylation, and miRNAs are critically involved in SLE pathogenesis [5, 6]. Being the most extensively studied epigenetic mechanism so far, DNA methylation regulates gene expression at the transcriptional level and is critically involved in the regulation of many key biological processes including embryonic development, genome expression, X-chromosome inactivation (XCI), genomic imprinting, and chromosome stability [7]. The recent genome-wide DNA methylation profiling studies revealed a persistent hypomethylation of Type I interferon-related genes in CD4+ T cells, suggesting an involvement of epigenetic mechanisms in heightened type I interferon signaling and sensitivity in lupus T cells [12, 13]. It is evident that DNA methylation plays a critical role in lupus pathogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
