DNA methylation 101: what is important to know about DNA methylation and its role in SLE risk and disease heterogeneity

Lanata, Cristina; Chung, Sharon A.; Criswell, Lindsey A.

doi:10.1136/lupus-2018-000285

Cited by 45 publications

(46 citation statements)

References 175 publications

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“…The HLA-DR2 and HLA-DR3 alleles have also been associated with susceptibility and autoantibody production in lupus 12–15 . Overall, hypomethylation of interferon-responsive genes has been associated with higher disease activity and renal disease, as well as production of autoantibodies 16–18 . For example, differentially methylated CpGs in TNK2, DUSP5, MAN1C1, PLEKHA1, IRF7, HIF3A, IFI44, and PRR4 have been associated with lupus nephritis 18–20 .…”

Section: Introductionmentioning

confidence: 99%

“…Overall, hypomethylation of interferon-responsive genes has been associated with higher disease activity and renal disease, as well as production of autoantibodies 16–18 . For example, differentially methylated CpGs in TNK2, DUSP5, MAN1C1, PLEKHA1, IRF7, HIF3A, IFI44, and PRR4 have been associated with lupus nephritis 18–20 . Differentially methylated CpGs in IFIT1, IFI44L, MX1, RSAD2, OAS1, EIF2AK2 , PARP9/DTX3L , and RABGAP1L have been associated with production of autoantibodies 16,21,22 .…”

Section: Introductionmentioning

confidence: 99%

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A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus

et al. 2019

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Systemic lupus erythematous (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. Here, we aim to identify SLE subgroups within a multiethnic cohort using an unsupervised clustering approach based on the American College of Rheumatology (ACR) classification criteria. We identify three patient clusters that vary according to disease severity. Methylation association analysis identifies a set of 256 differentially methylated CpGs across clusters, including 101 CpGs in genes in the Type I Interferon pathway, and we validate these associations in an external cohort. A cis-methylation quantitative trait loci analysis identifies 744 significant CpG-SNP pairs. The methylation signature is enriched for ethnic-associated CpGs suggesting that genetic and non-genetic factors may drive outcomes and ethnic-associated methylation differences. Our computational approach highlights molecular differences associated with clusters rather than single outcome measures. This work demonstrates the utility of applying integrative methods to address clinical heterogeneity in multifactorial multi-ethnic disease settings.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus

et al. 2019

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“…Although the effects of IFNs on DNA methylation are not well understood, several studies have reported altered DNA-methylation patterns, including hypomethylation of ISGs in SLE blood cells, which may augment gene expression and thus an IFN signature (reviewed in ref. 70 ). These reports support further investigation of epigenomic signatures and the relationships among IFN signaling, chromatin changes and DNA methylation in autoimmune disease cells.…”

Section: Consequences Of Epigenomic Remodeling By Ifnsmentioning

confidence: 99%

Interferon target-gene expression and epigenomic signatures in health and disease

2019

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Multiple type I interferons and interferon-γ (IFN-γ) are expressed under physiological conditions and are increased by stress and infections, and in autoinflammatory and autoimmune diseases. Interferons activate the Jak-STAT signaling pathway and induce overlapping patterns of expression, called 'interferon signatures', of canonical interferon-stimulated genes (ISGs) encoding molecules important for antiviral responses, antigen presentation, autoimmunity and inflammation. It has now become clear that interferons also induce an 'interferon epigenomic signature' by activating latent enhancers and 'bookmarking' chromatin, thus reprogramming cell responses to environmental cues. The interferon epigenomic signature affects ISGs and other gene sets, including canonical targets of the transcription factor NF-κB that encode inflammatory molecules, and is involved in the priming of immune cells, tolerance and the training of innate immune memory. Here we review the mechanisms through which interferon signatures and interferon epigenomic signatures are generated, as well as the expression and functional consequences of these signatures in homeostasis and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis.

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“…Epigenetic changes are prominent in cells and tissues from patients with SLE and a recent, comprehensive review summarises DNA methylation studies in SLE 75. Patients with SLE have decreased methylation levels in a large number of CpG sites and the most strongly hypomethylated genes are IFN regulated 76.…”

Section: Introductionmentioning

confidence: 99%

Interferon pathway in SLE: one key to unlocking the mystery of the disease

2019

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SLE is characterised by an activation of the interferon (IFN) system, which leads to an increased expression of IFN-regulated genes. The reasons behind the IFN signature in SLE are (1) the existence of endogenous IFN inducers, (2) activation of several IFN-producing cell types, (3) production of many different IFNs, (4) a genetic setup promoting IFN production and (5) deficient negative feedback mechanisms. The consequences for the immune system is a continuous stimulation to an immune response, and for the patient a number of different organ manifestations leading to typical symptoms for SLE. In the current review, we will present the existing knowledge of the IFN system and pathway activation in SLE. We will also discuss how this information can contribute to our understanding of both the aetiopathogenesis and some organ manifestations of the disease. We will put forward some issues that are unresolved and should be clarified in order to make a proper stratification of patients with SLE, which seems important when selecting a therapy aiming to downregulate the IFN system.

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DNA methylation 101: what is important to know about DNA methylation and its role in SLE risk and disease heterogeneity

Cited by 45 publications

References 175 publications

A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus

A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus

Interferon target-gene expression and epigenomic signatures in health and disease

Interferon pathway in SLE: one key to unlocking the mystery of the disease

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