Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients

doi:10.1016/J.JAUT.2013.04.003

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Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients

Journal Article•DOI•

Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients

Patrick Coit¹, Matlock A. Jeffries², Nezam Altorok¹, Mikhail G. Dozmorov³, Kristi A. Koelsch³, Jonathan D. Wren⁴, Jonathan D. Wren³, Joan T. Merrill³, W. Joseph McCune¹, Amr H. Sawalha¹ - Show less +6 more•Institutions (4)

University of Michigan¹, University of Oklahoma², Oklahoma Medical Research Foundation³, University of Oklahoma Health Sciences Center⁴

01 Jun 2013-Journal of Autoimmunity (NIH Public Access)-Vol. 43, pp 78-84

TL;DR: The data suggest epigenetic "poising" of interferon-regulated genes in l upus naïve CD4+ T cells, argue for a novel pathogenic implication for abnormal T cell DNA methylation in lupus, and suggest a mechanism for type-I interferons hyper-responsiveness in lUPus T cells.

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About: This article is published in Journal of Autoimmunity.The article was published on 2013-06-01 and is currently open access. It has received 267 citations till now. The article focuses on the topics: DNA methylation & Systemic lupus erythematosus.

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Journal Article•DOI•

New insights into the immunopathogenesis of systemic lupus erythematosus

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George C. Tsokos¹, Mindy S. Lo², Patrícia Costa Reis, Kathleen E. Sullivan³•Institutions (3)

Beth Israel Deaconess Medical Center¹, Boston Children's Hospital², Children's Hospital of Philadelphia³

01 Dec 2016-Nature Reviews Rheumatology

TL;DR: Improved understanding of the pathogenesis of SLE is driving a renewed interest in targeted therapy, and researchers are now on the verge of developing targeted immunotherapy directed at treating either specific organ system involvement or specific subsets of patients with SLE.

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Abstract: In this Review, Tsokos et al. describe recent advances in our understanding of systemic lupus erythematosus (SLE) that are driving repurposing of existing drugs as well as development of new treatments. Cytokines, tolerance pathways, local tissue mediators, and epigenetic mechanisms all show promise as novel targeted therapies that could lead to individualized care in SLE.

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766 citations

Journal Article•DOI•

Systemic lupus erythematosus.

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Arvind Kaul¹, Caroline Gordon², Mary K. Crow³, Zahi Touma⁴, Murray B. Urowitz⁴, Ronald F van Vollenhoven⁵, Guillermo Ruiz-Irastorza⁶, Graham R. V. Hughes⁷ - Show less +4 more•Institutions (7)

St George's, University of London¹, University of Birmingham², Hospital for Special Surgery³, Toronto Western Hospital⁴, Karolinska Institutet⁵, University of the Basque Country⁶, London Bridge Hospital⁷

16 Jun 2016

TL;DR: The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucose-sparing regimes.

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Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

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737 citations

Journal Article•DOI•

Type I Interferon in the Pathogenesis of Lupus

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Mary K. Crow¹•Institutions (1)

Hospital for Special Surgery¹

15 Jun 2014-Journal of Immunology

TL;DR: Genetic association data support the conclusion that many of the immunologic and pathologic features of this disease are a consequence of a persistent self-directed immune reaction driven by IFN-I and mimicking a sustained antivirus response.

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Abstract: Investigations of patients with systemic lupus erythematosus have applied insights from studies of the innate immune response to define IFN-I, with IFN-α as the dominant mediator, as central to the pathogenesis of this prototype systemic autoimmune disease. Genetic association data identify regulators of nucleic acid degradation and components of TLR-independent, endosomal TLR-dependent, and IFN-I-signaling pathways as contributors to lupus disease susceptibility. Together with a gene expression signature characterized by IFN-I-induced gene transcripts in lupus blood and tissue, those data support the conclusion that many of the immunologic and pathologic features of this disease are a consequence of a persistent self-directed immune reaction driven by IFN-I and mimicking a sustained antivirus response. This expanding knowledge of the role of IFN-I and the innate immune response suggests candidate therapeutic targets that are being tested in lupus patients.

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411 citations

Cites background from "Genome-wide DNA methylation study s..."

...Recent data from epigenetic analyses of hypomethylated genome sites support activation of many genes related to IFN-I signaling (22, 23)....
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Journal Article•DOI•

Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective

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Vaishali R. Moulton¹, Abel Suárez-Fueyo¹, Esra Meidan¹, Esra Meidan², Hao Li¹, Masayuki Mizui³, George C. Tsokos¹ - Show less +3 more•Institutions (3)

Beth Israel Deaconess Medical Center¹, Boston Children's Hospital², Osaka University³

01 Jul 2017-Trends in Molecular Medicine

TL;DR: Novel observations have provided an improved understanding of the contribution of tissue-specific factors and associated damage, T and B lymphocytes, as well as innate immune cell subsets and their corresponding abnormalities.

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288 citations

Journal Article•DOI•

Accounting for Population Stratification in DNA Methylation Studies

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Richard Barfield¹, Lynn M. Almli², Varun Kilaru², Alicia K. Smith², Kristina B. Mercer², Richard Duncan², Torsten Klengel³, Divya Mehta³, Elisabeth B. Binder³, Michael P. Epstein², Kerry J. Ressler², Karen N. Conneely² - Show less +8 more•Institutions (3)

Harvard University¹, Emory University², Max Planck Society³

01 Apr 2014-Genetic Epidemiology

TL;DR: Among the different approaches to computing methylation‐based PCs, it is found that PCs based on CpG sites chosen for their potential to proxy nearby SNPs can provide a powerful and computationally efficient approach to adjust for population stratification in DNA methylation studies when genome‐wide SNP data are unavailable.

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Abstract: DNA methylation is an important epigenetic mechanism that has been linked to complex diseases and is of great interest to researchers as a potential link between genome, environment, and disease. As the scale of DNA methylation association studies approaches that of genome-wide association studies, issues such as population stratification will need to be addressed. It is well-documented that failure to adjust for population stratification can lead to false positives in genetic association studies, but population stratification is often unaccounted for in DNA methylation studies. Here, we propose several approaches to correct for population stratification using principal components (PCs) from different subsets of genome-wide methylation data. We first illustrate the potential for confounding due to population stratification by demonstrating widespread associations between DNA methylation and race in 388 individuals (365 African American and 23 Caucasian). We subsequently evaluate the performance of our PC-based approaches and other methods in adjusting for confounding due to population stratification. Our simulations show that (1) all of the methods considered are effective at removing inflation due to population stratification, and (2) maximum power can be obtained with single-nucleotide polymorphism (SNP)-based PCs, followed by methylation-based PCs, which outperform both surrogate variable analysis and genomic control. Among our different approaches to computing methylation-based PCs, we find that PCs based on CpG sites chosen for their potential to proxy nearby SNPs can provide a powerful and computationally efficient approach to adjust for population stratification in DNA methylation studies when genome-wide SNP data are unavailable.

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223 citations

Cites background from "Genome-wide DNA methylation study s..."

...…addition to environmental stressors such as smoking and age [Alisch et al., 2012; Breitling et al., 2011; Christensen et al., 2009; Cicek et al., 2013; Coit et al., 2013; Numata et al., 2012; Rakyan et al., 2010; Selamat et al., 2012; Sun et al., 2013; Teschendorff et al., 2010; Wong et al., 2013]....
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...Through these studies, altered DNA methylation has been linked to diseases such as cancer, autism, and lupus in addition to environmental stressors such as smoking and age [Alisch et al., 2012; Breitling et al., 2011; Christensen et al., 2009; Cicek et al., 2013; Coit et al., 2013; Numata et al., 2012; Rakyan et al., 2010; Selamat et al., 2012; Sun et al., 2013; Teschendorff et al., 2010; Wong et al., 2013]....
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References

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Open Access

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Journal Article•DOI•

Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.

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Peter L. Jones¹, Gert C. Jan Veenstra¹, Paul A. Wade¹, Danielle Vermaak¹, Stefan U. Kass², Nicoletta Landsberger, John Strouboulis¹, Alan P. Wolffe¹ - Show less +4 more•Institutions (2)

National Institutes of Health¹, Janssen Pharmaceutica²

01 Jun 1998-Nature Genetics

TL;DR: The results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.

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Abstract: CpG methylation in vertebrates correlates with alterations in chromatin structure and gene silencing. Differences in DNA-methylation status are associated with imprinting phenomena and carcinogenesis. In Xenopus laevis oocytes, DNA methylation dominantly silences transcription through the assembly of a repressive nucleosomal array. Methylated DNA assembled into chromatin binds the transcriptional repressor MeCP2 which cofractionates with Sin3 and histone deacetylase. Silencing conferred by MeCP2 and methylated DNA can be relieved by inhibition of histone deacetylase, facilitating the remodelling of chromatin and transcriptional activation. These results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.

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2,726 citations

"Genome-wide DNA methylation study s..." refers background in this paper

...DNA methylation induces chromatin inaccessibility by several mechanisms, including recruitment of histone deacetylases that remove acetyl groups from histone tails thereby increasing the charge attraction between DNA and histone proteins to generate more compact chromatin configuration that prevents access by the transcriptional machinery [4]....
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Journal Article•DOI•

Cutting Edge: Autoimmune Disease Risk Variant of STAT4 Confers Increased Sensitivity to IFN-α in Lupus Patients In Vivo

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Silvia N. Kariuki¹, Kyriakos A. Kirou², Emma MacDermott², Lilliana Barillas-Arias², Mary K. Crow², Timothy B. Niewold¹ - Show less +2 more•Institutions (2)

University of Chicago¹, Hospital for Special Surgery²

01 Jan 2009-Journal of Immunology

TL;DR: The risk variant of STAT4 (T allele; rs7574865) was simultaneously associated with both lower serum IFN-α activity and greater IFn-α-induced gene expression in PBMC in SLE patients in vivo, and STAT4 showed dominant influence on the sensitivity of PBMC to serum IFM-α.

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Abstract: Increased IFN-α signaling is a primary pathogenic factor in systemic lupus erythematosus (SLE). STAT4 is a transcription factor that is activated by IFN-α signaling, and genetic variation of STAT4 has been associated with risk of SLE and rheumatoid arthritis. We measured serum IFN-α activity and simultaneous IFN-α-induced gene expression in PBMC in a large SLE cohort. The risk variant of STAT4 (T allele; rs7574865) was simultaneously associated with both lower serum IFN-α activity and greater IFN-α-induced gene expression in PBMC in SLE patients in vivo. Regression analyses confirmed that the risk allele of STAT4 was associated with increased sensitivity to IFN-α signaling. The IFN regulatory factor 5 SLE risk genotype was associated with higher serum IFN-α activity; however, STAT4 showed dominant influence on the sensitivity of PBMC to serum IFN-α. These data provide biologic relevance for the risk variant of STAT4 in the IFN-α pathway in vivo.

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222 citations

"Genome-wide DNA methylation study s..." refers background in this paper

...least a subset of lupus patients have been previously shown to have increased sensitivity to interferon-alpha [11]....
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Journal Article•DOI•

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

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Matlock A. Jeffries¹, Mikhail G. Dozmorov², Yuhong Tang, Joan T. Merrill², Jonathan D. Wren², Amr H. Sawalha³, Amr H. Sawalha², Amr H. Sawalha⁴ - Show less +4 more•Institutions (4)

University of Oklahoma Health Sciences Center¹, Oklahoma Medical Research Foundation², University of Oklahoma³, Veterans Health Administration⁴

01 May 2011-Epigenetics

TL;DR: Data suggest that the methylation status of RAB22A, STX1B2, LGALS3BP, DNASE1L1 and PREX1 correlates with disease activity in lupus patients, and protein-protein interaction maps identified a transcription factor, HNF4a, as a regulatory hub affecting a number of differentially methylated genes.

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Abstract: Systemic lupus erythematosus is a chronic-relapsing autoimmune disease of incompletely understood etiology. Recent evidence strongly supports an epigenetic contribution to the pathogenesis of lupus. To understand the extent and nature of dysregulated DNA methylation in lupus T cells, we performed a genome-wide DNA methylation study in CD4+ T cells in lupus patients compared to normal healthy controls. Cytosine methylation was quantified in 27,578 CG sites located within the promoter regions of 14,495 genes. We identified 236 hypomethylated and 105 hypermethylated CG sites in lupus CD4+ T cells compared to normal controls, consistent with widespread DNA methylation changes in lupus T cells. Of interest, hypomethylated genes in lupus T cells include CD9, which is known to provide potent T-cell co-stimulation signals. Other genes with known involvement in autoimmunity such as MMP9 and PDGFRA were also hypomethylated. The BST2 gene, an interferon-inducible membrane-bound protein that helps restrict the releas...

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214 citations

"Genome-wide DNA methylation study s..." refers background or methods in this paper

...DNA methylation analysis was performed using GenomeStudio methylation analysis package (Illumina) as previously described [6]....
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...003 majority of the differentially methylated genes in CD4þ Tcells from lupus patients were hypomethylated, consistent with a methylation defect previously described in lupus T cells [1,6]....
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...We have previously reported hypomethylation and overexpression of BST2 in total CD4þ T cells from lupus patients [6]....
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...Bisulfite DNA sequencing was used to validate the DNA methylation array results in a number of known hypermethylated and hypomethylated loci in the genome as described previously [6] in all the samples included in the discovery set (cohort 1)....
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...Validation of the array data was performed using bisulfite DNA sequencing in known hypermethylated and hypomethylated regions as previously described [6]....
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Journal Article•DOI•

Impaired DNA methylation and its mechanisms in CD4(+)T cells of systemic lupus erythematosus.

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Yiqun Zhang¹, Ming Zhao¹, Amr H. Sawalha², Bruce Richardson², Qianjin Lu¹, Qianjin Lu³ - Show less +2 more•Institutions (3)

Central South University¹, University of Michigan², Chinese Ministry of Education³

01 Mar 2013-Journal of Autoimmunity

TL;DR: Current understanding of T cell DNA methylation changes and the consequently altered gene expressions in lupus are summarized, and how they contribute to the development of SLE is summarized.

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163 citations

Journal Article•DOI•

Interferon alpha as a primary pathogenic factor in human lupus.

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Timothy B. Niewold¹•Institutions (1)

University of Chicago¹

08 Dec 2011-Journal of Interferon and Cytokine Research

TL;DR: Evidence support the idea that genetically determined endogenous elevations in IFN-α predispose to human SLE, and that risk of SLE is a burden the authors have taken on in the fight to defend ourselves against viral infection.

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Abstract: Interferon alpha (IFN-α) is a critical mediator of human systemic lupus erythematosus (SLE). This review will summarize evidence supporting the role for IFN-α in the initiation of human SLE. IFN-α functions in viral immunity at the interface of innate and adaptive immunity, a position well suited to setting thresholds for autoimmunity. Some individuals treated with IFN-α for chronic viral infections develop de novo SLE, which frequently resolves when IFN-α is withdrawn, supporting the idea that IFN-α was causal. Abnormally high IFN-α levels are clustered within SLE families, suggesting that high serum IFN-α is a heritable risk factor for SLE. Additionally, SLE-risk genetic variants in the IFN-α pathway are gain of function in nature, resulting in either higher circulating IFN-α levels or greater sensitivity to IFN-α signaling in SLE patients. A recent genome-wide association study has identified additional novel genetic loci associated with high serum IFN-α in SLE patients. These data support the idea that genetically determined endogenous elevations in IFN-α predispose to human SLE. It is possible that some of these gain-of-function polymorphisms in the IFN-α pathway are useful in viral defense, and that risk of SLE is a burden we have taken on in the fight to defend ourselves against viral infection.

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134 citations

"Genome-wide DNA methylation study s..." refers background in this paper

...Naïve CD4þ T cells were separated from PBMCs using the Naive CD4þ T Cell Isolation Kit II (Miltenyi Biotec, Cambridge, MA) which allows for the indirect isolation of untouched naïve CD4þ T cells....
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...Indeed, PBMCs from at thylation study suggests epigenetic accessibility and transcriptional patients, Journal of Autoimmunity (2013), http://dx.doi.org/10.1016/ least a subset of lupus patients have been previously shown to have increased sensitivity to interferon-alpha [11]....
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...Naïve CD4þ T cell isolation and purity Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood samples obtained from patients and controls using density gradient centrifugation (Amersham Biosciences, Uppsala, Sweden)....
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...Indeed, type-I interferon is strongly emphasized among differentially methylated genes in agreement with the interferon expression signature described in lupus PBMCs [9,10]....
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