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DNA Methylation 101: What Is Important to Know About DNA Methylation and Its Role in SLE Risk and Disease Heterogeneity

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DNA Methylation 101: What Is Important to Know About DNA Methylation and Its Role in SLE Risk and Disease Heterogeneity Review Lupus Sci Med: first published as 10.1136/lupus-2018-000285 on 25 July 2018. Downloaded from DNA methylation 101: what is important to know about DNA methylation and its role in SLE risk and disease heterogeneity Cristina M Lanata, Sharon A Chung, Lindsey A Criswell To cite: Lanata CM, Chung SA, ABSTRACT in gene regulation that lead to disease, and Criswell LA. DNA methylation SLE is a complex autoimmune disease that results from it has been hypothesised as a mechanism 101: what is important to the interplay of genetics, epigenetics and environmental contributing to the missing heritability of know about DNA methylation exposures. DNA methylation is an epigenetic mechanism and its role in SLE risk and SLE. Among all the epigenetic modifica- that regulates gene expression and tissue differentiation. disease heterogeneity. tions, DNA methylation perturbations have Among all the epigenetic modifications, DNA methylation Lupus Science & Medicine been the most widely studied in SLE.4 DNA perturbations have been the most widely studied in 2018;5:e000285. doi:10.1136/ methylation can be transmitted from parent lupus-2018-000285 SLE. It mediates processes relevant to SLE, including 5 lymphocyte development, X-chromosome inactivation to daughter cells, indicating that this form and the suppression of endogenous retroviruses. The of epigenetic modification could represent a Received 18 June 2018 establishment of most DNA methylation marks occurs molecular mediator capable of propagating Accepted 25 June 2018 in utero; however, a small percentage of epigenetic marks the memory of past cellular perturbations.6 In are dynamic and can change throughout a person’s this review, we summarise the current under- lifetime and in relation to exposures. In this review, we standing of mechanisms of DNA methylation, discuss the current understanding of the biology of technical considerations related to its meas- DNA methylation and its regulators, the measurement urement and interpretation, and the current and interpretation of methylation marks, the effects of genetics on DNA methylation and the role of environmental understanding relating it to SLE risk and exposures with relevance to SLE. We also summarise disease heterogeneity. research findings associated with SLE disease risk and http://lupus.bmj.com/ heterogeneity. The robust finding of hypomethylation of Definition of epigenetics interferon-responsive genes in patients with SLE and new Epigenetic processes modify gene expres- associations beyond interferon-responsive genes such as cell-specific methylation abnormalities are described. sion without changing the DNA sequence We also discuss methylation changes associated with of the gene. The definition of epigenetics lupus nephritis, autoantibody status and disease activity. has evolved substantially. In the 1950s, the Lastly, we explore future research directions, emphasising concept of epigenetic systems as mediators of the need for longitudinal studies, cell tissue and context- cellular memory and cellular identity arose.7 on September 24, 2021 by guest. Protected copyright. specific profiling, as well as integrative approaches. With In the 1970s, DNA methylation was proposed new technologies, DNA methylation perturbations could be to be a transcriptional regulatory mecha- targeted and edited, offering novel therapeutic approaches. nism that could be maintained through cell division.8 9 By linking DNA methylation to INTRODUCTION an epigenetic phenomenon, the definition © Author(s) (or their In the last 20 years, there have been major of epigenetics became a molecular one. The employer(s)) 2018. Re-use advances in our understanding of the under- development of next-generation sequencing permitted under CC BY-NC. No lying genetic risk for SLE, with >80 estab- for studying DNA methylation and other regu- commercial re-use. See rights lished susceptibility loci.1 As our knowledge latory processes genome-wide has resulted in and permissions. Published by BMJ. advances, the estimated heritability of SLE further evolution of the definition of epige- 2 netics to encompass virtually all genome-wide Russell/Engleman Rheumatology has increased from 12% to 43.9%. Never- Research Center, Department of theless, genetic factors do not fully explain chromatin modifications that do not change Medicine, University of California disease susceptibility, and environmental the underlying DNA sequence, including San Francisco, San Francisco, exposures such as smoking, ultraviolet (UV) DNA methylation, histone modifications, California, USA light, infections, the microbiome, virome, diet chromatin accessibility, microRNA regula- Correspondence to and stressful events have all been associated tions and two-dimensional chromatin interac- 3 10 Professor Lindsey A Criswell; with disease risk. Epigenetic modifications tions. Such changes in DNA and chromatin lindsey. criswell@ ucsf. edu may link environmental exposures to changes structure correlate with changes in chromatin Lanata CM, et al. Lupus Science & Medicine 2018;5:e000285. doi:10.1136/lupus-2018-000285 1 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2018-000285 on 25 July 2018. Downloaded from http://lupus.bmj.com/ Figure 1 DNA methylation and demethylation. Representation of DNA methylation: The addition of a methyl group at the fifth carbon position of the cytosine base. This process is mediated by the DNA methyltransferase (DNMT) enzyme family. DNA demethylation is mediated by the ten eleven translocation (TET) enzyme family. Active demethylation is a sequential process in which 5-methylcytosine is converted to 5-hydroxymethylcytosine (5-hmC), which is converted to 5-formylcytosine (5-fC) and finally 5-carboxylcytosine (5-caC). This process readies the sites for thymine-DNA glycosylase (TDG) to remove both 5-fC and 5-caC. BER, base excision repair; OG, oxoglutarate; SAH, S-adenosyl-L-homocysteine; SAM, S-adenosyl-L-methionine. Adapted with permission from Martin et al.105 on September 24, 2021 by guest. Protected copyright. accessibility and transcription factor binding, which can DNA methylation and transcriptional regulation lead to changes in gene expression. Among these, DNA methylation is the best-studied epigenetic modification in Key points SLE. ► DNA methylation occurs in CpG nucleotides that are distributed un- DNA methylation evenly across the genome. DNA methylation occurs when a methyl group is added ► DNA methylation patterns are cell and tissue specific. to the fifth carbon of cytosine residues that are linked by ► Methylation of CpGs in the promoter region is associated with gene a phosphate to a guanine nucleotide (a CpG dinucleo- repression. tide) by DNA methyltransferases (DNMT1, DNMT3A ► Hypomethylation in the promoter region and hypermethylation in the and DNMT3B). This addition forms 5-methylcytosine gene body are associated with gene expression. (figure 1).11 The methyl group is obtained from the methyl ► Methyl-binding proteins localise to methylated DNA to form inactive donor S adenosine methionine (SAM). SAM levels are and compact heterochromatin. influenced by dietary intake of vitamins such as folic acid, vitamin B12 and pyridoxal phosphate (vitamin B6). CpG DNA methylation effects on transcriptional regula- dinucleotides are methylated in a tissue and cell-type-spe- tion differ depending on the location of the CpG site cific manner, and their methylation critically influences (intragenic vs promoter region vs enhancer). Most cell differentiation and tissue development.12 13 of the genome does not contain CpG sites. However, 2 Lanata CM, et al. Lupus Science & Medicine 2018;5:e000285. doi:10.1136/lupus-2018-000285 Review Lupus Sci Med: first published as 10.1136/lupus-2018-000285 on 25 July 2018. Downloaded from Figure 2 A schematic representation of the genome. White CpG sites reflect non-methylated CpG sites. Black represents methylated CpG sites. Gene expression can occur in the setting of unmethylated CpG sites in the promoter region and methylated CpG sites at the gene body (genic). Adapted with permission from Stirzaker et al.14 clusters of CpG sites, termed ‘CpG islands’, occur and MBD2 has been linked to immune system function commonly span promoters of house-keeping genes. and studied in the context of autoimmunity. Although These promoter CpG islands typically remain unmeth- loss of MBD2 results in reduced numbers of T regula- ylated, resulting in active gene expression (CpG island, tory (Treg) cells, MBD2 null mice surprisingly do not promoter; figure 2).14 Methylated CpG island promoters develop autoimmunity. In humans, increased levels are associated with gene repression. CpG island ‘shores’ of MBD2 and global demethylation in CD4+T cells are regions of comparatively low CpG density, located have been observed in several autoimmune disorders, approximately 2 kb from CpG islands. Shores also including SLE.19 20 However, considerable effort will be exhibit tissue-specific differential methylation and required to fully understand the complexities of MBD2 methylation of shores is associated with gene silencing. function in autoimmunity. Gene bodies tend to have intermediate CpG densi- ties. Unlike CpG island promoters, extensive exonic Establishing and maintaining DNA methylation marks or genic methylation is typically associated with active gene expression. Beyond these regions, the genome has a lower-than-expected frequency of CpG sites which Key points are typically methylated (intergenic; figure 2). This http://lupus.bmj.com/
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