Cell lineage-specific genome-wide DNA methylation analysis of patients with paediatric-onset systemic lupus erythematosus

Yeung, Kit San; Lee, Tsz Leung; Mok, Mo Yin; Mak, Christopher Chun Yu; Yang, Wanling; Chong, Patrick Chun Yin; Lee, Pamela; Ho, Marco Hok Kung; Choufani, Sanaa; Lau, Chak Sing; Lau, Yu Lung; Weksberg, Rosanna

doi:10.1080/15592294.2019.1585176

Cited by 19 publications

(15 citation statements)

References 45 publications

(83 reference statements)

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“…Recent studies have identified that DNA hypomethylation might contribute to the immune response and over-reactivity in SLE CD4 + T cells (Zhang et al, 2013;Zhao et al, 2014;Yeung et al, 2019). In addition, biochemical modifications to mRNA, especially m 6 A and m 5 C, have also been shown to be of considerable importance with regard to the biological functions of developing disease (Li et al, 2018;.…”

Section: Discussionmentioning

confidence: 99%

“…Loss of the normal balance of activity in CD4 + T cells is associated with the development of SLE (Yin et al, 2015). In addition, epigenetics-based genetic predispositions and their interaction in T cells are thought to contribute to SLE pathogenesis and development (Lei et al, 2009;Yeung et al, 2019); these epigenetic modulators include DNA methylation, DNA 5-hmC, and altered long non-coding RNA expression (Coit et al, 2015;Zhao et al, 2016;Zhang et al, 2018;Guo et al, 2019;Ye et al, 2019). For example, the transcription factor RFX1 affects the epigenetic status of CD4 + T cells, which result in autoimmune responses in SLE (Zhao et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Disease Activity-Associated Alteration of mRNA m5 C Methylation in CD4+ T Cells of Systemic Lupus Erythematosus

Guo

Wang

Shi

et al. 2020

Front. Cell Dev. Biol.

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Epigenetic processes including RNA methylation, post-translational modifications, and non-coding RNA expression have been associated with the heritable risks of systemic lupus erythematosus (SLE). In this study, we aimed to explore the dysregulated expression of 5-methylcytosine (m 5 C) in CD4 + T cells from patients with SLE and the potential function of affected mRNAs in SLE pathogenesis. mRNA methylation profiles were ascertained through chromatography-coupled triple quadrupole mass spectrometry in CD4 + T cells from two pools of patients with SLE exhibiting stable activity, two pools with moderate-to-major activity, and two pools of healthy controls (HCs). Simultaneously, mRNA methylation profiles and expression profiling were performed using RNA-Bis-Seq and RNA-Seq, respectively. Integrated mRNA methylation and mRNA expression bioinformatics analysis was comprehensively performed. mRNA methyltransferase NSUN2 expression was validated in CD4 + T cells from 27 patients with SLE and 28 HCs using real-time polymerase chain reaction and western blot analyses. Hypomethylated-mRNA profiles of NSUN2-knockdown HeLa cells and of CD4 + T cells of patients with SLE were jointly analyzed using bioinformatics. Eleven methylation modifications (including elevated Am, 3 OMeA, m 1 A, and m 6 A and decreased , m 3 C, m 1 G, m 5 U, and t 6 A levels) were detected in CD4 + T cells of patients with SLE. Additionally, decreased m 5 C levels, albeit increased number of m 5 C-containing mRNAs, were observed in CD4 + T cells of patients with SLE compared with that in CD4 + T cells of HCs. m 5 C site distribution in mRNA transcripts was highly conserved and enriched in mRNA translation initiation sites. In particular, hypermethylated m 5 C or/and significantly up-regulated genes in SLE were significantly involved in immune-related and inflammatory pathways, including immune system,

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disease Activity-Associated Alteration of mRNA m5 C Methylation in CD4+ T Cells of Systemic Lupus Erythematosus

Guo

Wang

Shi

et al. 2020

Front. Cell Dev. Biol.

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“…Similar findings were reported by others, demonstrating reduced DNA methylation, and increased mRNA expression of type I IFN associated genes in B cells, T cells, monocytes and granulocytes (16). Reduced CpG DNA methylation of type I IFN associated genes is (expectedly) also present in juvenile-onset SLE (123) and contributes to increased type I IFN-induced gene expression patterns (116). Neutrophils, which exhibit even higher IFN-induced gene signatures as compared to other leukocytes (117), have 68% of their CpG sites hypomethylated and 32% hypermethylated (124).…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

The Role of Epigenetics in Autoimmune/Inflammatory Disease

2019

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Historically, systemic self-inflammatory conditions were classified as either autoinflammatory and caused by the innate immune system or autoimmune and driven by adaptive immune responses. However, it became clear that reality is much more complex and that autoimmune/inflammatory conditions range along an “inflammatory spectrum” with primarily autoinflammatory vs. autoimmune conditions resembling extremes at either end. Epigenetic modifications influence gene expression and alter cellular functions without modifying the genomic sequence. Methylation of CpG DNA dinucleotides and/or their hydroxymethylation, post-translational modifications to amino termini of histone proteins, and non-coding RNA expression are main epigenetic events. The pathophysiology of autoimmune/inflammatory diseases has been closely linked with disease causing gene mutations (rare) or a combination of genetic susceptibility and epigenetic modifications arising from exposure to the environment (more common). Over recent years, progress has been made in understanding molecular mechanisms involved in systemic inflammation and the contribution of innate and adaptive immune responses. Epigenetic events have been identified as (i) central pathophysiological factors in addition to genetic disease predisposition and (ii) as co-factors determining clinical pictures and outcomes in individuals with monogenic disease. Thus, a complete understanding of epigenetic contributors to autoimmune/inflammatory disease will result in approaches to predict individual disease outcomes and the introduction of effective, target-directed, and tolerable therapies. Here, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune/inflammatory disorders along the inflammatory spectrum choosing three examples: the autoinflammatory bone condition chronic nonbacterial osteomyelitis (CNO), the “mixed pattern” disorder psoriasis, and the autoimmune disease systemic lupus erythematosus (SLE).

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“…Se ha descrito en varios estudios, en pacientes con LES, la alteración en la porción larga del cromosoma 1, de manera específica la región 1q23-24. No se conoce por completo el mecanismo por el cual los genes de la región del complejo mayor de histocompatibilidad (HLA) podrían determinar la susceptibilidad al LES 1,5,6 . 2.…”

Section: Factores Predisponentes Y Desencadenantes Del Leunclassified

Lupus eritematoso. Vías de señalización en la inmunopatogenia y sus implicaciones terapéuticas

Jimnez-Prez¹,

Snchez²,

Fras-Mndez³

et al. 2021

MCUT

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El lupus eritematoso es una enfermedad autoinmunitaria, inflamatoria, crónica, multiorgánica y multifactorial. Se caracteriza por una reacción de hipersensibilidad tipo III, con depósitos de inmunocomplejos y activación del sistema de complemento. Es una enfermedad epigenética, relacionada con fenómenos desencadenantes que contribuyen a la inmunopatogenia de la enfermedad: ambientales, genéticos y hormonales, que favorecen la pérdida de la tolerancia inmunológica. Los mecanismos por los cuales se desarrolla la enfermedad incluyen producción de autoanticuerpos, hiperreactividad de linfocitos B, formación de complejos inmunitarios, deficiencias del sistema del complemento, activación de las células dendríticas plasmocitoides, aumento de los valores de interferones y citocinas, y disfunción apoptótica. En los últimos años ha cobrado gran relevancia la alteración en la vía de señalización de las cinasas Janus como factor predisponente de la etiopatogenia. Una amplia variedad de fármacos se ha administrado en el control y tratamiento de la enfermedad. El futuro de la terapéutica se enfoca en medicamentos dirigidos a la modulación inmunológica, entre ellos inhibidores del factor activador de linfocitos B, antiinterferones tipo I, antiinterferones α e inhibidores de la señalización a través de las cinasas Janus. Se revisan los factores predisponentes y desencadenantes del lupus eritematoso, su efecto en las vías de señalización inmunológica y el posible blanco terapéutico en el diseño de nuevos fármacos capaces de modular el sistema inmunitario para el control de la enfermedad.

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Cell lineage-specific genome-wide DNA methylation analysis of patients with paediatric-onset systemic lupus erythematosus

Cited by 19 publications

References 45 publications

Disease Activity-Associated Alteration of mRNA m5 C Methylation in CD4+ T Cells of Systemic Lupus Erythematosus

Disease Activity-Associated Alteration of mRNA m5 C Methylation in CD4+ T Cells of Systemic Lupus Erythematosus

The Role of Epigenetics in Autoimmune/Inflammatory Disease

Lupus eritematoso. Vías de señalización en la inmunopatogenia y sus implicaciones terapéuticas

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