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Clinical value of DNA methylation markers in autoimmune rheumatic diseases

Nature Reviews Rheumatology volume 16, pages 514–524 (2020)Cite this article

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Abstract

Methylation of cytosine residues in DNA, the best studied epigenetic modification, is associated with gene transcription and nuclear organization, and ultimately the function of a cell. DNA methylation can be influenced by various factors, including changes in neighbouring genomic sites such as those induced by transcription factor binding. The DNA methylation profiles in relevant cell types are altered in most human diseases compared with the healthy state. Given the physical stability of DNA and methylated DNA compared with other epigenetic modifications, DNA methylation is an ideal marker for clinical purposes. However, few DNA methylation-based markers have made it into clinical practice, with the notable exception of some markers used in the field of oncology. Autoimmune rheumatic diseases are genetically complex entities that can vary widely in terms of prognosis, subtypes, progression and treatment responses. Increasing reports showing strong links between DNA methylation profiles and different clinical outcomes and other clinical aspects in autoimmune rheumatic diseases reinforce the usefulness of DNA methylation profiles as novel clinical markers. In this Review, we provide an updated discussion on DNA methylation alterations in autoimmune rheumatic diseases and the advantages and disadvantages of using these markers in clinical practice.

Key points

  • DNA methylation patterns are cell type specific, and particular patterns are associated with gene transcription and cellular function; aberrant DNA methylation profiles are associated with pathogenic cell phenotypes.

  • Genetic susceptibility variants and environmental cues, in conjunction with nuclear factors, can influence the DNA methylation profiles of immune cells.

  • Particular DNA methylation alterations are associated with the subtype, activity, progression and/or response to therapy of various autoimmune rheumatic diseases.

  • The stability of methylated cytosines, and their physical association with the DNA, make these markers ideally suited for clinical purposes.

  • For the future development of practical and useful DNA methylation-based markers, further studies that include large cohorts of patients and relevant cell types are needed.

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Fig. 1: Genetic and environment influences on DNA methylation.
Fig. 2: Clinical applications for DNA methylation markers in autoimmune rheumatic disease.

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Acknowledgements

The authors thank O. Morante-Palacios and C. de la Calle-Fabregat for their help with the figures. The authors also thank CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. E.B. is funded by the Ministry of Science, Innovation and Universities (MCIU) (grant numbers SAF2017-88086-R; AEI/FEDER, UE). Q.L. is funded by the National Natural Science Foundation of China (grant numbers 81830097 and 81861138016) and the Research and Development Plan of key areas in Hunan Province (grant number 2019WK2081). A.H.S is funded by the National Institutes of Health (grants numbers R01AI097134 and R01AR070148) and the Lupus Research Alliance.

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Authors and Affiliations

  1. Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain

    Esteban Ballestar

  2. Division of Rheumatology, Department of Pediatrics; Division of Rheumatology and Clinical Immunology, Department of Medicine, Lupus Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA

    Amr H. Sawalha

  3. Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

    Qianjin Lu

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E.B. wrote the article. All authors researched data for the article, provided substantial contributions to discussions of content and reviewed and/or edited the article before submission.

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Nature Reviews Rheumatology thanks C. Hedrich, M. Alarcon-Riquelme and P. Ramos for their contribution to the peer review of this work.

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Glossary

DNA methylation

The covalent attachment of a methyl group to a DNA residue (most commonly to a cytosine nucleotide followed by a guanine nucleotide, known as CpG sites).

Methylation quantitative trait loci

Genetic variants that are associated with DNA methylation levels at particular CpG sites.

Synovial fibroblasts

Also known as fibroblast-like synoviocytes, synovial fibroblasts are the main stromal cells of the joint synovium. These cells produce the extracellular matrix components of the synovial fluid and are critical for cartilage integrity and lubrication of the joint.

Regulatory T cells

(Treg cells). A subpopulation of T cells that are immunosuppressive and generally suppress proliferation of effector T cells; these cells are essential for preventing autoimmune disease.

Genome-wide association studies

Observational studies of genome-wide sets of genetic variants in different individuals to identify variants associated with a trait; these studies typically focus on associations between single nucleotide polymorphisms and the occurrence of a disease.

Differentially methylated region

Genomic regions with a differential DNA methylation status across different biological samples. Differentially methylated regions usually involve adjacent sites or a group of sites close together.

Whole-genome bisulfite sequencing

A next-generation sequencing-based method for assessing the DNA methylation level of all cytosines in a genome, using sodium bisulfite treatment and DNA sequencing.

Reduced representation bisulfite sequencing

A method for analysing the DNA methylation profiles of genome regions that have a high CpG content using a combination of restriction enzyme digestion and bisulfite next-generation sequencing.

DNA methylation bead arrays

A high-throughput microarray-based method for measuring DNA methylation levels at single CpG site resolution.

Bisulfite pyrosequencing

A method designed to quantitatively determine the methylation status of individual cytosines in CpG sites from short PCR amplicons of DNA pre-treated with sodium bisulfite.

Epigenome-wide association study

An observational study examining a genome-wide set of epigenetic marks, including DNA methylation, and their association with a particular phenotype or trait (such as the occurrence of a disease).

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Ballestar, E., Sawalha, A.H. & Lu, Q. Clinical value of DNA methylation markers in autoimmune rheumatic diseases. Nat Rev Rheumatol 16, 514–524 (2020). https://doi.org/10.1038/s41584-020-0470-9

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