Epigenetic Mechanisms Implicated in the Pathogenesis of Systemic Lupus Erythematosus Disease: A Topic Review
DOI:
https://doi.org/10.17533/udea.iatreia.330Keywords:
Acetylation, Epigenomic, Methylation, MicroRNA, Systemic Lupus ErythematosusAbstract
Introduction: Systemic Lupus Erythematosus (SLE) is a prevalent autoimmune disease characterized by a dysregulated immune response against multiple autoantigens. The etiology of SLE is complex and multifactorial, and epigenetics has emerged as a relevant factor associated with the onset of clinical manifestations.
Objective: To analyze and describe the epigenetic mechanisms associated with the pathophysiology of SLE.
Methods: A literature review was conducted to identify associations between epigenetic mechanisms and the pathophysiology of SLE, with emphasis on the recognition of key markers.
Results: Downregulation of DNA methylation allows the expression of genes that increase susceptibility to autoantigen presentation and autoantibody generation. Likewise, modifications of histones H3K4me1 and H3Kme2 facilitate chromatin decondensation, enhancing the transcription of genes that promote cell growth and proliferation, such as CDKN2A, PTPN22, and LRP1B, while condensing the chromatin of regulatory genes such as RUNX3. Finally, miR-146a, miR-21, and miR-148a are associated with abnormal inflammatory cascades, alterations in the interferon pathway, and DNA methylation.
Conclusions: Epigenetic mechanisms are key determinants in the onset of autoimmune diseases and reflect the environmental susceptibility observed in these conditions.
Downloads
References
(1) Budhram A, Chu R, Rusta-Sallehy S, Ioannidis G, Denburg JA, Adachi JD, et al. Anti-cyclic citrullinated peptide antibody as a marker of erosive arthritis in patients with systemic lupus erythematosus: a systematic review and meta-analysis. Lupus [Internet]. 2014;23(11):1156-1163. https://doi.org/10.1177/0961203314540967
(2) Jameson JL, Fauci AS, Kasper DL Hauser SL, Longo DL, Loscalzo J. Harrison's principles of internal medicine. 20th edition. New York: McGraw-Hill Education; 2018.
(3) Fernández-Ávila DG, Bernal-Macías S, Rincón-Riaño DN, Gutiérrez Dávila JM, Rosselli D. Prevalence of systemic lupus erythematosus in Colombia: data from the national health registry 2012-2016. Lupus [Internet]. 2019 Sep;28(10):1273-1278. https://doi.org/10.1177/0961203319864168
(4) Rivera, M. Epidemiología y características demográficas del lupus cutáneo en Colombia según datos del registro nacional de salud de Colombia 2015 – 2019 [Tesis]. Bogotá: Pontificia Universidad Javeriana. 2022. Disponible en: http://hdl.handle.net/10554/63077
(5) Bentham J, Morris DL, Graham DSC, Pinder CL, Tombleson P, Behrens TW, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet [Internet]. 2015;47(12):1457-1464. https://doi.org/10.1038/ng.3434
(6) James JA, Kim-Howard XR, Bruner BF, Jhonsson MK, McClain MT, Arbuckle MR, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus [Internet]. 2007;16(6):401-409. https://doi.org/10.1177/0961203307078579
(7) Adelman ER, Huang HT, Roisman A, Olsson A, Colaprico A, Qin T, et al. Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia. Cancer Discov [Internet]. 2019; 9 (8): 1080–1101. https://doi.org/10.1158/2159-8290.CD-18-1474
(8) Absher DM, Li X, Waite LL, Gibson A, Roberts K, Edberg J, et al. Genome-wide DNA methylation analysis of systemic lupus erythematosus reveals persistent hypomethylation of interferon genes and compositional changes to CD4+ T-cell populations. PLoS Genet [Internet]. 2013;9(8):e1003678. https://doi.org/10.1371/journal.pgen.1003678
(9) Gensterblum E, Renauer P, Coit P, Strickland FM, Kilian NC, Miller S, et al. CD4+CD28+KIR+CD11ahi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients. J Autoimmun [Internet]. 2018;86:19-28. https://doi.org/10.1016/j.jaut.2017.09.011
(10) Richardson B, Sawalha AH, Ray D, Yung R. Murine models of lupus induced by hypomethylated T cells (DNA hypomethylation and lupus…). Methods Mol Biol [Internet]. 2012; 900:169-180. https://doi.org/10.1007/978-1-60761-720-4_8
(11) Yung RL, Quddus J, Chrisp CE, Johnson KJ, Richardson BC. Mechanism of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. J Immunol [Internet]. 1995 Mar 15;154(6):3025-3035. https://doi.org/10.4049/jimmunol.154.6.3025
(12) Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY,et al. DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell [Internet]. 2015;162(5):961-973. https://doi.org/10.1016/j.cell.2015.07.056
(13) Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res [Internet]. 2010;20(2):170-179. doi: 10.1101/gr.100289.109.
(14) Lanata CM, Nititham J, Taylor KE, Solomon O, Chung SA, Blazer A, et al. Dynamics of Methylation of CpG Sites Associated With Systemic Lupus Erythematosus Subtypes in a Longitudinal Cohort. Arthritis Rheumatol. 2022 Oct;74(10):1676-1686. https://doi.org/10.1101/gr.100289.109
(15) Nguyen CT, Gonzales FA, Jones PA. Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation. Nucleic Acids Res [Internet]. 2001;29(22):4598-4606. https://doi.org/10.1093/nar/29.22.4598
(16) Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum [Internet]. 1990;33(11):1665-1673. https://doi.org/10.1002/art.1780331109
(17) Minning S, Xiaofan Y, Anqi X, Bingjie G, Dinglei S, Mingshun Z, et al. Imbalance between CD8+CD28+ and CD8+CD28- T-cell subsets and its clinical significance in patients with systemic lupus erythematosus. Lupus [Internet]. 2019;28(10):1214-1223. https://doi.org/10.1177/0961203319867130
(18) Strickland FM, Hewagama A, Wu A, Sawalha AH, Delaney C, Hoeltzel MF, et al. Diet influences expression of autoimmune-associated genes and disease severity by epigenetic mechanisms in a transgenic mouse model of lupus. Arthritis Rheum [Internet]. 2013;65(7):1872-1881. https://doi.org/10.1002/art.37967
(19) Vordenbaumen S, Sokolowski A, Rosenbaum A, Gebhard C, Raithel J, Dusing C, et al. Methyl donor micronutrients, CD40-ligand methylation and disease activity in systemic lupus erythematosus: a cross-sectional association study. Lupus [Internet]. 2021; 30(11): 1773–1780. https://doi.org/10.1177/09612033211034559
(20) Gravand A, Alesaeidi S, Khoshbakht S, Saghaei M, Kenarangi T, Mosallaei M, et al. Demethylation of CDKN2A in systemic lupus erythematosus and rheumatoid arthritis: a blood biomarker for diagnosis and assessment of disease activity. Clin Rheumatol [Internet]. 2023; 42(12): 3387-3395. https://doi.org/10.1007/s10067-023-06736-z
(21) Chen Z, Guo Y, Zhao D, Zou Q, Yu F, Zhang L, et al. Comprehensive Analysis Revealed that CDKN2A is a Biomarker for Immune Infiltrates in Multiple Cancers. Front Cell Dev Biol [Internet]. 2021; 9:808208. https://doi.org/10.3389/fcell.2021.808208
(22) Quddus J, Johnson KJ, Gavalchin J, Amento EP, Chrisp CE, Yung RL, et al. Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J Clin Invest [Internet]. 1993;92(1):38-53. https://doi.org/10.1172/jci116576
(23) Gu Z, Cao X, Jiang J, Li L, Da Z, Liu H, et al. Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. Cell Signal [Internet]. 2012;24(12):2307-2314. https://doi.org/10.1016/j.cellsig.2012.07.012
(24) de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C, et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med [Internet]. 1991;174(4):915-924. https://doi.org/10.1084/jem.174.4.915
(25) Imgenberg-Kreuz J, Almlöf JC, Leonard D, Sjöwall C, Syvänen AC, Rönnblom L, et al. Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjögren's Syndrome. Front Immunol [Internet]. 2019;10:1686. https://doi.org/10.3389/fimmu.2019.01686
(26) Imgenberg-Kreuz J, Carlsson-Almlöf J, Leonard D, Alexsson A, Nordmark G, Eloranta ML, et al. DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Ann Rheum Dis [Internet]. 2018;77(5):736-743. https://doi.org/10.1136/annrheumdis-2017-212379
(27) Pierce BA. Genética: Un enfoque conceptual. 5a Edición. España: Editorial Medica Panamericana; 2016.
(28) Millán-Zambrano G, Burton A, Bannister AJ, Schneider R. Histone post-translational modifications - cause and consequence of genome function. Nat Rev Genet [Internet]. 2022;23(9):563-580. https://doi.org/10.1038/s41576-022-00468-7
(29) Logie C, Tse C, Hansen JC, Peterson CL. The core histone N-terminal domains are required for multiple rounds of catalytic chromatin remodeling by the SWI/SNF and RSC complexes. Biochemistry [Internet]. 1999 ;38(8):2514-2522. https://doi.org/10.1021/bi982109d
(30) Ren J, Panther E, Liao X, Grammer AC, Lipsky PE, Reilly CM. The Impact of Protein Acetylation/Deacetylation on Systemic Lupus Erythematosus. Int J Mol Sci [Internet]. 2018;19(12):4007. https://doi.org/10.3390/ijms19124007
(31) Toussirot E, Abbas W, Khan KA, Tissot M, Jeudy A, Baud L, et al. Imbalance between HAT and HDAC activities in the PBMCs of patients with ankylosing spondylitis or rheumatoid arthritis and influence of HDAC inhibitors on TNF alpha production. PLoS One [Internet]. 2013;8(8):e70939. https://doi.org/10.1371/journal.pone.0070939
(32) Yang Y, Tang Q, Zhao M, Liang G, Wu H, Li D, et al. The effect of mycophenolic acid on epigenetic modifications in lupus CD4+T cells. Clin Immunol [Internet]. 2015 ;158(1):67-76. https://doi.org/10.1016/j.clim.2015.03.005
(33) Zhang Z, Song L, Maurer K, Petri MA, Sullivan KE. Global H4 acetylation analysis by ChIP-chip in systemic lupus erythematosus monocytes. Genes Immun [Internet]. 2010;11(2):124-133. https://doi.org/10.1038/gene.2009.66
(34) Zhang Z, Song L, Maurer K, Bagashev A, Sullivan KE. Monocyte polarization: the relationship of genome-wide changes in H4 acetylation with polarization. Genes Immun [Interent]. 2011;12(6):445-456. https://doi.org/10.1038/gene.2011.17
(35) Weckerle CE, Franek BS, Kelly JA, Kumabe M, Mikolaitis RA, Green SL, et al. Network analysis of associations between serum interferon-α activity, autoantibodies, and clinical features in systemic lupus erythematosus. Arthritis Rheum [Internet]. 2011;63(4):1044-1053. https://doi.org/10.1002/art.30187
(36) Dozmorov MG, Wren JD, Alarcón-Riquelme ME. Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes. Epigenetics [Internet]. 2014;9(2):276-285. https://doi.org/10.4161/epi.27021
(37) Trynka G, Sandor C, Han B, Xu H, Stranger BE, Liu SX, et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet [Internet]. 2013;45(2):124-130. https://doi.org/10.1038/ng.2504
(38) Dai Y, Zhang L, Hu C, Zhang Y. Genome-wide analysis of histone H3 lysine 4 trimethylation by ChIP-chip in peripheral blood mononuclear cells of systemic lupus erythematosus patients. Clin Exp Rheumatol [Internet]. 2010;28(2):158-168. Available from: https://www.clinexprheumatol.org/abstract.asp?a=264
(39) Y Zhou, X Qiu, Y Luo, Yuan J, Li Y, Zhong Q, et al., Histone modifications and methyl-CpG-binding domain protein levels at the TNFSF7 (CD70) promoter in SLE CD4+ T cells. Lupus [Internet]. 2011; 20(13): 1365–1371. https://doi.org/10.1177/0961203311413412
(40) Lu Q, Wu A, Richardson BC. Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. J Immunol [Internet]. 2005;174(10):6212-6219. https://doi.org/10.4049/jimmunol.174.10.6212
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Iatreia
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Papers published in the journal are available for use under the Creative Commons license, specifically Attribution-NonCommercial-ShareAlike 4.0 International.
The papers must be unpublished and sent exclusively to the Journal Iatreia; the author uploading the contribution is required to submit two fully completed formats: article submission and authorship responsibility.
