Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Clinical Reviews in Allergy & Immunology
Published in: Clinical Reviews in Allergy & Immunology 1/2010

01-08-2010

Epigenetics in Rheumatoid Arthritis

Authors: Michelle Trenkmann, Matthias Brock, Caroline Ospelt, Steffen Gay

Published in: Clinical Reviews in Allergy & Immunology | Issue 1/2010

Login to get access

Abstract

Epigenetics is a steadily growing research area. In many human diseases, especially in cancers, but also in autoimmune diseases, epigenetic aberrations have been found. Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints. Even though the etiology is not yet fully understood, rheumatoid arthritis is generally considered to be caused by a combination of genetic predisposition, deregulated immunomodulation, and environmental influences. To gain a better understanding of this disease, researchers have become interested in studying epigenetic changes in rheumatoid arthritis. Here, we want to review the current knowledge on epigenetics in rheumatoid arthritis.
Literature
1.
2.
3.
Ospelt C, Gay S (2008) The role of resident synovial cells in destructive arthritis. Best Pract Res Clin Rheumatol 22:239–252PubMedCrossRef
4.
Smith JB, Haynes MK (2002) Rheumatoid arthritis—a molecular understanding. Ann Intern Med 136:908–922PubMed
5.
Ermann J, Fathman CG (2001) Autoimmune diseases: genes, bugs and failed regulation. Nat Immunol 2:759–761PubMedCrossRef
6.
7.
8.
Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–440PubMedCrossRef
9.
10.
Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447:407–412PubMedCrossRef
11.
Lee GR, Kim ST, Spilianakis CG, Fields PE, Flavell RA (2006) T helper cell differentiation: regulation by cis elements and epigenetics. Immunity 24:369–379PubMedCrossRef
12.
Su IH, Tarakhovsky A (2005) Epigenetic control of B cell differentiation. Semin Immunol 17:167–172PubMedCrossRef
13.
De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130:1083–1094PubMedCrossRef
14.
Bhaumik SR, Smith E, Shilatifard A (2007) Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 14:1008–1016PubMedCrossRef
15.
16.
Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42PubMedCrossRef
17.
18.
Smith BC, Denu JM (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta 1789:45–57PubMed
19.
Chang B, Chen Y, Zhao Y, Bruick RK (2007) JMJD6 is a histone arginine demethylase. Science 318:444–447PubMedCrossRef
20.
Wang Y, Wysocka J, Sayegh J et al (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306:279–283PubMedCrossRef
21.
Sadoul K, Boyault C, Pabion M, Khochbin S (2008) Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie 90:306–312PubMedCrossRef
22.
Huang J, Berger SL (2008) The emerging field of dynamic lysine methylation of non-histone proteins. Curr Opin Genet Dev 18:152–158PubMedCrossRef
23.
Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A (2002) T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol 3:643–651PubMedCrossRef
24.
Baguet A, Bix M (2004) Chromatin landscape dynamics of the Il4-Il13 locus during T helper 1 and 2 development. Proc Natl Acad Sci U S A 101:11410–11415PubMedCrossRef
25.
Koyanagi M, Baguet A, Martens J, Margueron R, Jenuwein T, Bix M (2005) EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in Th1 cells. J Biol Chem 280:31470–31477PubMedCrossRef
26.
Chang S, Aune TM (2007) Dynamic changes in histone-methylation ‘marks’ across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. Nat Immunol 8:723–731PubMedCrossRef
27.
Raza K, Falciani F, Curnow SJ et al (2005) Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther 7:R784–R795PubMedCrossRef
28.
Vittecoq O, Lequerre T, Goeb V, Le Loet X, Abdesselam TA, Klemmer N (2008) Smoking and inflammatory diseases. Best Pract Res Clin Rheumatol 22:923–935PubMedCrossRef
29.
Yang SR, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I (2007) Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am J Physiol Lung Cell Mol Physiol 292:L567–L576PubMedCrossRef
30.
Kawahara TL, Michishita E, Adler AS et al (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136:62–74PubMedCrossRef
31.
Van Gool F, Galli M, Gueydan C et al (2009) Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat Med 15:206–210PubMedCrossRef
32.
Grabiec AM, Tak PP, Reedquist KA (2008) Targeting histone deacetylase activity in rheumatoid arthritis and asthma as prototypes of inflammatory disease: should we keep our HATs on? Arthritis Res Ther 10:226PubMedCrossRef
33.
Nishida K, Komiyama T, Miyazawa S et al (2004) Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 50:3365–3376PubMedCrossRef
34.
Lin HS, Hu CY, Chan HY et al (2007) Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol 150:862–872PubMedCrossRef
35.
Nakamura T, Kukita T, Shobuike T et al (2005) Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN-beta production. J Immunol 175:5809–5816PubMed
36.
37.
Nasu Y, Nishida K, Miyazawa S et al (2008) Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthritis Cartilage 16:723–732PubMedCrossRef
38.
Huber LC, Brock M, Hemmatazad H et al (2007) Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum 56:1087–1093PubMedCrossRef
39.
Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26:5541–5552PubMedCrossRef
40.
Nakashima K, Hagiwara T, Yamada M (2002) Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem 277:49562–49568PubMedCrossRef
41.
Zendman AJ, van Venrooij WJ, Pruijn GJ (2006) Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology (Oxford) 45:20–25CrossRef
42.
Chang X, Yamada R, Suzuki A et al (2005) Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford) 44:40–50CrossRef
43.
Vossenaar ER, Radstake TR, van der Heijden A et al (2004) Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis 63:373–381PubMedCrossRef
44.
45.
Wang Y, Li M, Stadler S et al (2009) Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol 184:205–213PubMedCrossRef
46.
Neeli I, Khan SN, Radic M (2008) Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol 180:1895–1902PubMed
47.
Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97PubMedCrossRef
48.
Chiang PK, Gordon RK, Tal J et al (1996) S-Adenosylmethionine and methylation. FASEB J 10:471–480PubMed
49.
Bird AP, Wolffe AP (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99:451–454PubMedCrossRef
50.
Bruniquel D, Schwartz RH (2003) Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 4:235–240PubMedCrossRef
51.
Sullivan KE, Reddy AB, Dietzmann K et al (2007) Epigenetic regulation of tumor necrosis factor alpha. Mol Cell Biol 27:5147–5160PubMedCrossRef
52.
McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442PubMedCrossRef
53.
Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33:1665–1673PubMedCrossRef
54.
Neidhart M, Rethage J, Kuchen S et al (2000) Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum 43:2634–2647PubMedCrossRef
55.
Nile CJ, Read RC, Akil M, Duff GW, Wilson AG (2008) Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 58:2686–2693PubMedCrossRef
56.
57.
Otterson GA, Khleif SN, Chen W, Coxon AB, Kaye FJ (1995) CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza 2′deoxycytidine. Oncogene 11:1211–1216PubMed
58.
Katzenellenbogen RA, Baylin SB, Herman JG (1999) Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 93:4347–4353PubMed
59.
Dobrovic A, Simpfendorfer D (1997) Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57:3347–3350PubMed
60.
Kang SH, Choi HH, Kim SG et al (2000) Transcriptional inactivation of the tissue inhibitor of metalloproteinase-3 gene by dna hypermethylation of the 5′-CpG island in human gastric cancer cell lines. Int J Cancer 86:632–635PubMedCrossRef
61.
Takami N, Osawa K, Miura Y et al (2006) Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum 54:779–787PubMedCrossRef
62.
63.
Wang GG, Allis CD, Chi P (2007) Chromatin remodeling and cancer. Part II: ATP-dependent chromatin remodeling. Trends Mol Med 13:373–380PubMedCrossRef
64.
65.
66.
67.
68.
Ozcelik T (2008) X chromosome inactivation and female predisposition to autoimmunity. Clin Rev Allergy Immunol 34:348–351PubMedCrossRef
69.
Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B (2007) Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 179:6352–6358PubMed
70.
Uz E, Loubiere LS, Gadi VK et al (2008) Skewed X-chromosome inactivation in scleroderma. Clin Rev Allergy Immunol 34:352–355PubMedCrossRef
71.
72.
Moazed D (2009) Small RNAs in transcriptional gene silencing and genome defence. Nature 457:413–420PubMedCrossRef
73.
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854PubMedCrossRef
74.
75.
Faller M, Guo F (2008) MicroRNA biogenesis: there's more than one way to skin a cat. Biochim Biophys Acta 1779:663–667PubMed
76.
Mendell JT (2005) MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle 4:1179–1184PubMed
77.
Zeng Y, Yi R, Cullen BR (2003) MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci U S A 100:9779–9784PubMedCrossRef
78.
Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20PubMedCrossRef
79.
Cloonan N, Brown MK, Steptoe AL et al (2008) The miR-17–5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol 9:R127PubMedCrossRef
80.
Cimmino A, Calin GA, Fabbri M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102:13944–13949PubMedCrossRef
81.
Kim HK, Lee YS, Sivaprasad U, Malhotra A, Dutta A (2006) Muscle-specific microRNA miR-206 promotes muscle differentiation. J Cell Biol 174:677–687PubMedCrossRef
82.
O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A 104:1604–1609PubMedCrossRef
83.
Seibl R, Birchler T, Loeliger S et al (2003) Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 162:1221–1227PubMed
84.
Stanczyk J, Pedrioli DM, Brentano F et al (2008) Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 58:1001–1009PubMedCrossRef
85.
Ceppi M, Pereira PM, Dunand-Sauthier I et al (2009) MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A 106:2735–2740PubMedCrossRef
86.
Nakasa T, Miyaki S, Okubo A et al (2008) Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 58:1284–1292PubMedCrossRef
87.
Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK (2008) Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 10:R101PubMedCrossRef
88.
Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103:12481–12486PubMedCrossRef
89.
Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455:58–63PubMedCrossRef
90.
Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102:10604–10609PubMedCrossRef
91.
92.
Arnheim N, Calabrese P (2009) Understanding what determines the frequency and pattern of human germline mutations. Nat Rev Genet 10:478–488PubMedCrossRef
93.
Barros SP, Offenbacher S (2009) Epigenetics: connecting environment and genotype to phenotype and disease. J Dent Res 88:400–408PubMedCrossRef
94.
Figueiredo LM, Cross GA, Janzen CJ (2009) Epigenetic regulation in African trypanosomes: a new kid on the block. Nat Rev Microbiol 7:504–513PubMedCrossRef
95.
Hewagama A, Richardson B (2009) The genetics and epigenetics of autoimmune diseases. J Autoimmun 33:3–11PubMedCrossRef
96.
97.
Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M (2009) Female predominance and X chromosome defects in autoimmune diseases. J Autoimmun 33:12–16PubMedCrossRef
98.
Larizza D, Calcaterra V, Martinetti M (2009) Autoimmune stigmata in Turner syndrome: when lacks an X chromosome. J Autoimmun 33:25–30PubMedCrossRef
99.
Persani L, Rossetti R, Cacciatore C, Bonomi M (2009) Primary Ovarian Insufficiency: X chromosome defects and autoimmunity. J Autoimmun 33:35–41PubMedCrossRef
100.
Sawalha AH, Harley JB, Scofield RH (2009) Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes. J Autoimmun 33:31–34PubMedCrossRef
101.
Wells AD (2009) New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol 182:7331–7341PubMedCrossRef
102.
Zernicka-Goetz M, Morris SA, Bruce AW (2009) Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo. Nat Rev Genet 10:467–477PubMedCrossRef
Metadata
Title
Epigenetics in Rheumatoid Arthritis
Authors
Michelle Trenkmann
Matthias Brock
Caroline Ospelt
Steffen Gay
Publication date
01-08-2010
Publisher
Humana Press Inc
Published in
Clinical Reviews in Allergy & Immunology / Issue 1/2010
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI
https://doi.org/10.1007/s12016-009-8166-6

Other articles of this Issue 1/2010

Clinical Reviews in Allergy & Immunology 1/2010 Go to the issue

OriginalPaper

Autoreactive B Cells and Epigenetics

OriginalPaper

Epigenetic Histone Code and Autoimmunity

OriginalPaper

The Role of Epigenetics in Aging and Autoimmunity

OriginalPaper

X Chromosome Inactivation and Autoimmunity

OriginalPaper

The Human Endogenous Retrovirus Link between Genes and Environment in Multiple Sclerosis and in Multifactorial Diseases Associating Neuroinflammation

OriginalPaper

Epigenetics Lessons from Twins: Prospects for Autoimmune Disease
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits