Epigenetics and Systemic Lupus Erythematosus: Unmet Needs

Meroni, Pier Luigi; Penatti, Alessandra

doi:10.1007/s12016-015-8497-4

Cited by 30 publications

(14 citation statements)

References 88 publications

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“…While for some epigenetic alterations (particularly histone modifications and miRNAs) epigenetic treatment appears within reach, targeted alteration of DNA methylation appears even more complex [165]. However, epigenetic events cannot easily be dissected into DNA methylation, histone modifications and miRNA expression, since epigenetic events affect one another and epigenetic patterns can be 'translated' [14,16,17].…”

Section: Epigenetic Alterations As Biomarkers For Slementioning

confidence: 99%

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DNA Methylation in Systemic Lupus Erythematosus

et al. 2016

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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease facilitated by aberrant immune responses directed against cells and tissues, resulting in inflammation and organ damage. In the majority of patients, genetic predisposition is accompanied by additional factors conferring disease expression. While the exact molecular mechanisms remain elusive, epigenetic alterations in immune cells have been demonstrated to play a key role in disease pathogenesis through the dysregulation of gene expression. Since epigenetic marks are dynamic, allowing cells and tissues to differentiate and adjust, they can be influenced by environmental factors and also be targeted in therapeutic interventions. Here, we summarize reports on DNA methylation patterns in SLE, underlying molecular defects and their effect on immune cell function. We discuss the potential of DNA methylation as biomarker or therapeutic target in SLE.

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Section: Epigenetic Alterations As Biomarkers For Slementioning

confidence: 99%

“…Interactions between DNA methylation and other epigenetic events are briefly discussed. A detailed discussion of involved mechanisms, however, is beyond the scope of this manuscript and reviewed elsewhere [16,17].…”

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confidence: 99%

DNA Methylation in Systemic Lupus Erythematosus

et al. 2016

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“…Currently, our advanced understanding of the genetic mechanism underlying SLE indicated that epigenetic changes, such as disease-associated susceptibility gene regulation, noncoding RNA regulation, and post-transcriptional modifications (Meroni and Penatti, 2016;Mazzone et al, 2019), play important roles in SLE. For example, our previous study demonstrated that abnormally expressed microRNAs and non-coding circular RNAs (circRNAs) are involved in SLE pathogenesis and are potential diagnostic markers (Guo et al, 2018(Guo et al, , 2019.…”

Section: Introductionmentioning

confidence: 99%

Epitranscriptomic N4-Acetylcytidine Profiling in CD4+ T Cells of Systemic Lupus Erythematosus

Guo

Shi

Wang

et al. 2020

Front. Cell Dev. Biol.

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The emerging epitranscriptome plays an essential role in autoimmune disease. As a novel mRNA modification, N4-acetylcytidine (ac 4 C) could promote mRNA stability and translational efficiency. However, whether epigenetic mechanisms of RNA ac 4 C modification are involved in systemic lupus erythematosus (SLE) remains unclear. Herein, we detected eleven modifications in CD4 + T cells of SLE patients using mass spectrometry (LC-MS/MS). Furthermore, using samples from four CD4 + T cell pools, we identified lower modification of ac 4 C mRNA in SLE patients as compared to that in healthy controls (HCs). Meanwhile, significantly lower mRNA acetyltransferase NAT10 expression was detected in lupus CD4 + T cells by RT-qPCR. We then illustrated the transcriptome-wide ac 4 C profile in CD4 + T cells of SLE patients by ac 4 C-RIP-Seq and found ac 4 C distribution in mRNA transcripts to be highly conserved and enriched in mRNA coding sequence regions. Using bioinformatics analysis, the 3879 and 4073 ac 4 C hyper-acetylated and hypoacetylated peaks found in SLE samples, respectively, were found to be significantly involved in SLE-related function enrichments, including multiple metabolic and transcription-related processes, ROSinduced cellular signaling, apoptosis signaling, and NF-κB signaling. Moreover, we demonstrated the ac 4 C-modified regulatory network of gene biological functions in lupus CD4 + T cells. Notably, we determined that the 26 upregulated genes with hyperacetylation played essential roles in autoimmune diseases and disease-related processes. Additionally, the unique ac 4 C-related transcripts, including USP18, GPX1, and RGL1, regulate mRNA catabolic processes and translational initiation. Our study identified novel dysregulated ac 4 C mRNAs associated with critical immune and inflammatory responses, that have translational potential in lupus CD4 + T cells. Hence, our findings reveal transcriptional significance and potential therapeutic targets of mRNA ac 4 C modifications in SLE pathogenesis.

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“…Although differences in several genes were reported, their clinical implications and relevance remain elusive. In fact, in PBC and all other autoimmune diseases, the results of genome‐wide association studies have been disappointing, and recent efforts have been directed to both deep sequencing and consideration of epigenetic events …”

Section: Genetic and Environmental Influences: Xenobiotic Modificatiomentioning

confidence: 99%

Toward solving the etiological mystery of primary biliary cholangitis

Tanaka

Leung

Young

et al. 2017

Hepatology Communications

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Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti‐mitochondrial antibody (AMA) autoantibody, female predominance, and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens recognized by AMA have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relatively high concordance rate in identical twins, genome‐wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed, including spontaneous models, models induced by chemical xenobiotic immunization, and by “designer” mice with altered interferon metabolism. Herein, we describe five such models, including 1) NOD.c3c4 mice, 2) dominant negative form of transforming growth factor receptor type II mice, 3) interleukin‐2R α−/− mice, 4) adenylate‐uridylate‐rich element Del−/− mice, and 5) 2‐octynoic acid‐conjugated bovine serum albumin immunized mice. Individually there is no perfect murine model, but collectively the models point to loss of tolerance to PDC‐E2, the major mitochondrial autoantigen, as the earliest event that occurs before clinical disease is manifest. Although there is no direct association of AMA titer and PBC disease progression, it is noteworthy that the triad of PBC monocytes, biliary apotopes, and AMA leads to an intense proinflammatory cytokine burst. Further, the recurrence of PBC after liver transplantation indicates that, due to major histocompatibility complex restriction, disease activity must include not only adaptive immunity but also innate immune mechanisms. We postulate that successful treatment of PBC may require a personalized approach with therapies designed for different stages of disease. (Hepatology Communications 2017;1:275–287)

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Epigenetics and Systemic Lupus Erythematosus: Unmet Needs

Cited by 30 publications

References 88 publications

DNA Methylation in Systemic Lupus Erythematosus

DNA Methylation in Systemic Lupus Erythematosus

Epitranscriptomic N4-Acetylcytidine Profiling in CD4+ T Cells of Systemic Lupus Erythematosus

Toward solving the etiological mystery of primary biliary cholangitis

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