The transcription factor EGR2 plays an important role in the expansion and function TCRα + CD4 - CD8 - double negative T cells in lpr lupus mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE306407 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:Our previous study demonstrated a significant upregulation of a large set of miRNAs at the genomic imprinted Dlk1-Dio3 locus in lymphocytes of diverse murine lupus-prone strains. The upregulation of Dlk1-Dio3 miRNAs in lupus-prone mice is correlated with the global DNA hypomethylation. In this study, by performing genome-wide DNA methylation analysis, we reported that Dlk1-Dio3 genomic region in CD4+ T cells of MRL/lpr mice was hypomethylated, further linking hypomethylation to the increased expression of Dlk1-Dio3 miRNAs in lupus. Then, we assessed the gene expression levels of enzymes that either write (DNA methyltransferases, DNMTs) or erase DNA methylation (Ten-eleven translation proteins, TETs) to understand the molecular contributor to the DNA hypomethylation in MRL/lpr CD4+ T cells. The expression levels of Dnmt1, Dnmt3b, Tet1, and Tet2 were significantly increased in CD4+ T cells of MRL/lpr mice, as well as in B6/lpr and B6.sle123 mice, compared to their respective control mice. These data indicate the significant involvement of the TETs-mediated active demethylation pathway rather than reduced DNMTs-mediated passive demethylation pathway in the hypomethylation of murine lupus CD4+ T cells. The transcription factor, early growth response 2 (EGR2) is critically involved in regulating T cell functions and autoimmunity. In this research, we found that Egr2 deletion in B6/lpr mice notably reduced methylation-sensitive Dlk1-Dio3 cluster miRNAs expression in CD4+ T cells. Surprisingly, even though EGR2 has been shown to induce DNA demethylation by recruiting TET2, we found that deleting Egr2 in B6/lpr mice induced a higher number of hypomethylated DMRs than hypermethylated DMRs at either whole genome or the Dlk1-Dio3 locus in CD4+ T cells of B6/lpr mice. These data are the first finding on the positive role of EGR2 on the expression of Dlk1-Dio3 cluster miRNAs in lupus mice. Given that Dlk1-Dio3 miRNAs target the major signaling pathways in autoimmunity, these data provide a new perspective in understanding the potential pathogenic role of upregulated EGR2 in lupus.
2023-12-04 | GSE242955 | GEO
Project description:In this study, miRNA expression in splenic lymphocytes from three genetically disparate lupus-prone mouse models (MRL-lpr, B6-lpr and NZB/WF1) were profiled. 49 miRNAs were found to be differentially expressed in MRL-lpr mice compared to MRL mice; and 24 miRNAs were differentially expressed in B6-lpr mice compared to B6 mice. Among these dysregulated miRNAs, we noted that 15 miRNAs were common to both lpr strains. Interestingly, microarray analysis of NZB/W and NZW at 3 months of age, an age when overt lupus disease is not evident in NZB/W mice, revealed that only one miRNA, miR-148a was significantly upregulated in NZB/W mice.
2011-12-17 | GSE22359 | GEO
Project description:In this study, miRNA expression in splenic lymphocytes from three genetically disparate lupus-prone mouse models (MRL-lpr, B6-lpr and NZB/WF1) were profiled. 49 miRNAs were found to be differentially expressed in MRL-lpr mice compared to MRL mice; and 24 miRNAs were differentially expressed in B6-lpr mice compared to B6 mice. Among these dysregulated miRNAs, we noted that 15 miRNAs were common to both lpr strains. Interestingly, microarray analysis of NZB/W and NZW at 3 months of age, an age when overt lupus disease is not evident in NZB/W mice, revealed that only one miRNA, miR-148a was significantly upregulated in NZB/W mice. The aim of this porject is to determine the common miRNA expression changes in splenocytes from different strains of murine lupus models. The splenocytes were prepared from genetically lupus-prone female mice including MRL/MpJ-Faslpr/J (MRL-lpr), NZBWF1/J (NZB/W), B6.MRL-Faslpr/J (B6-lpr) and their control mice MRL/MpJ (MRL), NZW/LacJ (NZW) and C57BL/6J (B6) mice (The Jackson laboratory, ME). Total RNAs, containing miRNAs were isolated from whole splenocytes using mirVana miRNA isolation kits (Ambion) following manufactory’s instructions and sent to LC Sciences (http://www.lcsciences.com/) for the microarray assay. The mouse miRNA array chips (Chip ID miRMouse 12.0 version), which included 617 unique, mature, mouse miRNA, based on the Sanger miRBase Release 12.0, were used in the assay.
2011-12-17 | E-GEOD-22359 | biostudies-arrayexpress
Project description:Histone deacetylase (HDAC) complexes regulate pathological gene programs during heart disease progression. The recently identified mitotic deacetylase complex (MiDAC), which includes DNTTIP1, ELMSAN1, and HDAC1/2, remains the least characterized among these complexes. ELMSAN1 has been implicated in left ventricular remodeling, and its global deletion in mice leads to heart malformation. To investigate its role in mouse heart, we generated cardiomyocyte-specific Elmsan1 knockout (ELM cKO) using αMHC driven Cre recombinase. We analyzed both male and female animals across three experimental groups: αMHC-Cre (Cre control), ELM fl/fl (floxed control) and ELM cKO. In male ELM cKO mice, ejection fraction (EF) was significantly reduced by 12 weeks (45.64±3.12%), compared to αMHC-Cre (55.91±1.29%) and ELM fl/fl (59.16±3.70%) controls. By 24 weeks, EF declined further to 20.79%±4.52, representing a reduction of 46.4% (p<0.01) and 62.1% (p<0.0001) compared to αMHC-Cre and ELM fl/fl mice respectively. The heart failure phenotype in ELM cKO mice was supported by cardiomyocyte hypertrophy morphology, ventricular dilation, and shortened lifespan. Female ELM cKO mice exhibited similar defects with delayed onset. To investigate early molecular changes, we performed RNA sequencing on pre-symptomatic hearts from 8-week-old mice. A total of 1055 genes were differentially expressed in ELM ckO hearts, with 460 upregulated and 595 downregulated. Gene enrichment analysis revealed suppression of tricarboxylic acid cycle and key cardiac genes. These transcriptional changes were accompanied by decreased mitochondrial respiratory chain complex proteins, ultrastructural mitochondrial abnormalities, and impaired calcium handling. Our study demonstrates that Elmsan1 is pivotal for maintaining the heart function and hemostasis with advanced age.
2025-07-30 | GSE301440 | GEO
Project description:Mesenchymal stem cell transplantation (MSCT) has been widely used to treat a variety of human diseases. However, the detailed mechanisms underlying its success are not fully understood. Here we show that MSCT rescues recipient bone marrow mesenchymal stem cell (BMMSC) function in Fas-deficient-MRL/lpr systemic lupus erythematosus (SLE) mice via a miR-29b/Dnmt1/Notch epigenetic cascade. Using the microRNA microarray, we found that MSCT could rescue the high level of miR-29b in the recipient BMMSCs of MRL/lpr mice. In the present study, mesenchymal stem cell transplantation (MSCT) was used to treat MRL/lpr mice. One week after the treatment, normal control MSCs from C3H/HeJ mice (C3H), recipient MSCs from untreated MRL/lpr mice (LPR) and recipient MSCs from MSCT-treated MRL/lpr mice (MSC) were used for total RNA extraction and microRNA microarray for analysis of microRNA expressions.
2014-03-20 | E-GEOD-55971 | biostudies-arrayexpress
Project description:Global DNA hypomethylation in CD4+ cells in SLE patients was suggested to play a key role in the pathogenesis. To identify new methylation-sensitive genes, we integrated genome-wide DNA methylation and mRNA profiling in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified Ctse, in which 13 methyl-CpGs within 583 bp region of intron 1 were hypomethylated, and mRNA upregulated in MRL compared with B6 mice. One of methyl-CpGs, mCGCG was hypomethylated and mutated to CGGG in MRL mice. Kaiso is known to bind mCGCG and we hypothesized that it represses expression of Ctse. The binding of Kaiso to mCGCG site in B6 was reduced in MRL mice revealed by ChIP-PCR. EL4 cells treated with 5-azaC and/or TSA showed the suppression of the binding of Kaiso to mCGCG motif and the overexpression of Ctse was demonstrated by qPCR. Ctse gene silencing by siRNA in EL4 cells resulted in reduction of IL-10 secretion. Accordingly, IL10 and CTSE mRNAs up-regulated in CD4+ T cells both in MRL mice and the patients with SLE. The hypomethylation of mCGCG motif, reduced recruitment of Kaiso, and increased expression of Ctse and Il-10 in CD4+ cells may be involved in the pathogenesis of SLE.
2017-08-13 | GSE102421 | GEO
Project description:Previous studies have reported that deletion of the transcription factor, early growth response protein 2 (EGR2), in normal C57BL/6 (B6) resulted in the development of lupus-like autoimmune disease. However, increased EGR2 expression has been noted in human and murine lupus, which challenges the notion of the autoimmune suppressive role of EGR2 in B6 mice. In this study, we derived both conditional EGR2-/-B6/lpr and EGR2-/-B6 mice to elucidate the immune and autoimmune regulatory roles of EGR2 in autoinflammation (B6/lpr) versus physiologically normal (B6) conditions. We found that conditional EGR2 deletion increased spleen weight, enhanced T cell activation and IFNγ production, and promoted germinal center B cells and LAG3+ regulatory T cells development in both B6/lpr and B6 mice. Nevertheless, EGR2 deletion also showed strikingly differential effects in these two strains on T lymphocyte subsets profile, Foxp3+ Tregs and plasma cell differentiation, anti-dsDNA autoantibodies and immunoglobulins production, and on the induction of IL-17 in in vitro activated splenocytes. Specifically, EGR2 deletion in B6/lpr mice significantly decreased serum levels of anti-dsDNA autoantibodies, total IgG, IgM, IgG1, and IgG2a with reduced plasma cells differentiation. Furthermore, EGR2 deletion in B6/lpr mice had no obvious effect on IgG immunocomplex deposition, medium caliber vessel, and glomeruli inflammation but increased complement C3 immunocomplex deposition and large caliber vessel inflammation in the kidneys. Importantly, we demonstrated that EGR2 deletion in B6/lpr mice significantly reduced pathogenic CD4-CD8-CD3+B220+ double negative T cells, which correlated with the reduced anti-dsDNA autoantibodies in serum and decreased IL-17 production in splenocytes of EGR2-/-B6/lpr mice. Together, our data strongly suggest that the role of EGR2 is complex. The immunoregulatory role of EGR2 varies at normal or autoinflammation conditions and should not be generalized in differential experimental settings.
| S-EPMC9241489 | biostudies-literature
Project description:Mesenchymal stem cell transplantation (MSCT) has been widely used to treat a variety of human diseases. However, the detailed mechanisms underlying its success are not fully understood. Here we show that MSCT rescues recipient bone marrow mesenchymal stem cell (BMMSC) function in Fas-deficient-MRL/lpr systemic lupus erythematosus (SLE) mice via rescuing their hypomethylated DNA profile. Using the methylation microarray, we found the global hypomethylation pattern in the recipient BMMSCs of MRL/lpr mice could be rescued by MSCT. In the present study, mesenchymal stem cell transplantation (MSCT) was used to treat MRL/lpr mice. One week after the treatment, normal control MSCs from C3H/HeJ mice (C3H), recipient MSCs from untreated MRL/lpr mice (LPR) and recipient MSCs from MSCT-treated MRL/lpr mice (MSC) were used for total DNA extraction and DNA methylation microarray for analysis of global genome methylation patterns.
2014-03-20 | E-GEOD-55970 | biostudies-arrayexpress
Project description:Dhps<fl/fl> mice and Dhps<fl/fl>;Vil1<cre/+> mice were infected or not with Citrobacter rodentium (10^9 bacteria/mouse) for 14 days, and cell lysates were prepared for analysis. A total of 4 mice per group were used for the following groups: (1) Vil1<+> no C. Rod; (2) Vil1<cre> no C. Rod; (3) Vil1<+> with C. Rod; (4) Vil1<cre> with C. Rod
2025-05-06 | PXD051536 | Pride
Project description:Mitochondrial calcium regulates bioenergetics but also serves as a trigger for cell death.1 With a sustained increase in catecholamine or a large increase in cytosolic calcium as occurs with ischemia, mitochondrial calcium can rise to high levels, leading to activation of the mitochondrial permeability transition pore, thus initiating cell death.1 Calcium uptake into mitochondria occurs via the MCU (mitochondrial calcium uniporter), which is regulated by 3 EF (EF hand protein) hand proteins, MICU (mitochondrial calcium uptake) 1, 2, and 3.2 MICU1/MCU ratios vary in different tissues,3 and alterations in substrate flux have been shown to regulate MICU1 levels altering MCU-mediated calcium uptake.4 MICU3 has generally been thought to function primarily in neuronal tissue where it is highly expressed and thus has been largely ignored in other tissues such as the heart. We performed quantitative proteomics using Tandem mass tag labeling coupled to liquid chromatography and tandem mass spectrometry to analyze MCU and MCU regulators in cardiac and hepatic mitochondria (Figure [A]). Normalizing MICU levels to MCU in heart and liver mitochondria, we found that the MICU1/MCU ratio was 0.75 in liver and 0.25 in heart, which is consistent with previous studies3; however, the MICU3/MCU ratio in heart is >3-fold higher than that found in liver. To confirm that the MICU3 we observed in heart mitochondria was not due to contamination by mitochondria from nerve tissue in heart, we isolated cardiomyocytes and compared the ratio of MICU3 to MCU in cardiomyocytes and heart mitochondria and found similar ratios (Figure [B]). These data suggest that MICU3 might play a role in regulating MCU in heart.
2021-11-23 | MSV000088439 | MassIVE