Review Article

Immunological Regulation of DNA Methylation and its Implication in Allograft Rejection

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September 11th, 2026

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1Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, 2Institute of Nephrology, Zhejiang University, 3Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University

In This Article

Summary

This review summarizes the role of DNA methylation in immune regulation and transplant rejection. DNA methylation regulates immune cell development and differentiation, modulates immune cell function, and may serve as a biomarker and therapeutic target for improving graft survival.

Abstract

Transplant rejection remains a major barrier to long-term graft survival and is driven by complex interactions between immune responses and molecular regulatory mechanisms. DNA methylation, a major epigenetic modification, plays an important role in regulating immune cell development, differentiation, maturation, and function. Aberrant DNA methylation can alter the expression of immune-related genes and influence the nature and intensity of immune responses. In transplantation, these changes may affect T cells, B cells, and innate immune cells involved in graft rejection. DNA methylation also contributes to the regulation of signaling pathways associated with immune activation, tolerance, and inflammatory responses. Changes in methylation patterns may therefore influence both the progression of rejection and the maintenance of graft function. This review summarizes current knowledge of DNA methylation in immune regulation and examines its implications for transplant rejection, with particular emphasis on thymic development, helper and cytotoxic T cells, regulatory T cells, B cells, innate immune cells, and signaling pathways. It also considers the potential relevance of DNA methylation as a biomarker and therapeutic target in transplantation. Understanding these epigenetic mechanisms may support the development of more precise approaches for assessing rejection risk, modulating immune responses, and improving long-term graft outcomes following solid organ transplantation.

Introduction

Immunology is the scientific discipline concerned with the structure and function of the immune system, including the mechanisms underlying immune responses and the maintenance of homeostasis following recognition of self and non-self components. The field also encompasses pathological processes arising from dysregulated immune function. The immune system performs three fundamental functions: defense, surveillance, and homeostasis. Together, these functions prevent the invasion of external pathogens and harmful substances, eliminate non-self components within the body, and maintain a stable internal immune environment. Based on the characteristics of immune responses, immunity is classified as innate or adaptive. Innate immunity provides a rapid, non-specific response to foreign pathogens, whereas adaptive immunity provides a highly specific response directed against particular antigens1,2. During an immune response, external and internal factors regulate the expression of genes associated with immune function. Such regulation involves classical genetic mechanisms as well as epigenetic modifications, forming a complex and dynamic transcriptional regulatory network3.

Traditional genetics focuses on changes in gene function resulting from alterations in DNA sequences, whereas epigenetics examines reversible and heritable changes in gene expression that occur without modifying the underlying DNA sequence. Environmental stimuli, including infections, chemical exposures, and pharmaceuticals, as well as internal factors such as cytokines and hormones, can alter the epigenetic landscape of genes. These changes regulate gene expression and ultimately shape cellular phenotypes and biological functions. Major epigenetic mechanisms controlling gene expression include DNA methylation, histone modification, chromatin remodeling, and non-coding RNA-mediated regulation. During early embryonic development, DNA methylation marks are almost completely erased and subsequently re-established during differentiation4,5. Precise removal and re-establishment of these epigenetic modifications are essential for normal cellular development, differentiation, and maturation. In contrast, aberrant epigenetic alterations can disrupt gene function and contribute to disease onset and progression6. DNA methylation patterns also change dynamically during the development and differentiation of T cells and B cells7,8. These findings highlight the critical role of epigenetic regulation in directing the differentiation of bone marrow hematopoietic stem cells into diverse immune cell lineages. Histone modifications regulate the differentiation and functional plasticity of monocytes/macrophages and helper T cells9,10,11,12,13,14 and influence key signaling pathways, including Toll-like receptor pathways15,16. The chromatin remodeler Mi-2beta is highly expressed in thymocytes and directly regulates CD4 gene expression and T cell development17. Non-coding RNAs also function as important regulators of immune responses. For example, interferon-γ (IFN-γ) plays a central role in host defense against intracellular bacterial infections, whereas miR-21 can suppress IFN-γ production by directly targeting IFN-γ mRNA18. Collectively, these findings emphasize the central role of epigenetic mechanisms in regulating immune responses.

Immune cells are central to immune function and represent key drivers of transplant rejection, a major determinant of graft survival19,20,21. Although extensive immunological studies have examined the mechanisms underlying transplant rejection, many aspects remain poorly understood22. Growing evidence also demonstrates critical roles for epigenetic mechanisms in immune cell development, differentiation, and maturation23,24. Examination of the molecular basis of transplant rejection from an epigenetic perspective may therefore support earlier intervention and prevention of transplant rejection and chronic allograft nephropathy following organ transplantation, with potential benefits for long-term graft survival. Among the various epigenetic modifications, DNA methylation represents the most stable mechanism regulating transcription in the mammalian genome25. Accordingly, this review examines the role of DNA methylation in immune cell development, differentiation, and function, as well as its involvement in acute rejection following organ transplantation.

Review and Perspective

1. DNA methylation and sequencing technology

DNA methylation uses S-adenosylmethionine as a methyl donor, and DNA methyltransferases catalyze the covalent addition of a methyl group to the fifth carbon of cytosine within CpG dinucleotides (cytosine–phosphate–guanine), thereby converting cytosine to 5-methylcytosine (5mC). This modification adds an additional regulatory layer to gene expression beyond the DNA sequence itself. In general, regions with low levels of methylation permit protein binding and support a chromatin structure that favors active gene transcription26. In contrast, methylated DNA regions can suppress gene transcription and expression by recruiting methyl-CpG-binding domain (MBD) proteins, promoting histone modifications and chromatin remodeling complexes, or directly blocking the binding of transcription factors and other DNA-binding proteins27,28,29. However, DNA methylation can also be associated with gene activation, particularly within gene body regions, where it positively correlates with gene expression. Although this relationship occurs less frequently, gene body methylation is common in ubiquitously expressed genes30,31.

The biological function of DNA methylation must be interpreted within its genomic context. CpG dinucleotides often cluster in regions called CpG islands, which are defined as DNA segments longer than 200 base pairs (bp), with a G+C content of at least 50% and an observed/expected (Obs/Exp) ratio of at least 0.632. In the mammalian genome, CpG dinucleotides are relatively rare and account for only about 1% of the genome. Approximately 60% of human gene promoters are associated with CpG islands, and these regions are typically unmethylated in normal cells. Only a small proportion (~6%) becomes methylated during early development or tissue differentiation33,34. CpG shores refer to regions within 2,000 bp upstream and downstream of CpG islands, and their methylation status closely correlates with transcriptional silencing. Approximately 70% of differentially methylated regions occur in CpG shores during methylation reprogramming23,35. In addition, most tissue-specific methylation occurs in shores rather than in CpG islands34,35. CpG shelves are located within 2,000 bp upstream and downstream of CpG shores, whereas the term “open sea” refers to all remaining genomic regions outside CpG islands, shores, and shelves.

DNA methylation occurs through two main processes: maintenance methylation and de novo methylation. Maintenance methylation primarily occurs during semiconservative DNA replication, when maintenance methyltransferases copy existing methylation patterns onto the daughter strand. DNMT1 serves as the principal maintenance methyltransferase; it preferentially targets hemimethylated DNA, represents the most abundant methyltransferase in cells, and is actively transcribed during the S phase of the cell cycle36. In contrast, de novo methylation establishes new methylation patterns independently of DNA replication by targeting previously unmethylated sites. DNMT3A and DNMT3B function as the primary de novo methyltransferases. They are highly expressed in embryonic stem cells and play essential roles in establishing methylation patterns during embryonic development, but their expression decreases as cells differentiate27. The DNMT3 family also includes DNMT3L, which lacks catalytic activity but is critical for establishing maternal genomic imprinting37. DNMT3L enhances the activity of DNMT3A and DNMT3B, thereby improving the efficiency of DNA methylation38. Across the genome, many methylated cytosines undergo DNA demethylation, particularly within gene body regions. Demethylation occurs through active and passive mechanisms. Active demethylation involves the oxidation of 5mC into its oxidized derivatives by TET enzymes39. In contrast, passive demethylation results from the gradual dilution of methylated cytosines during DNA replication when maintenance methyltransferase activity is absent40.

Because DNA methylation plays a central role in regulating gene transcription and expression, it has become a major focus of research over the past decade, driven in part by advances in methylation detection technologies. Based on differences in sample pretreatment, DNA methylation detection approaches can be broadly classified into three categories41. The first approach relies on methylation-sensitive restriction endonucleases, which selectively fail to cleave methylated DNA regions and thus generate fragments of different sizes depending on methylation status. The second approach enriches methylated DNA fragments using methylation-binding proteins or antibodies that specifically recognize 5-methylcytosine. The third approach uses bisulfite treatment to convert unmethylated cytosines into uracils while leaving methylated cytosines unchanged, enabling precise discrimination between methylated and unmethylated sites. Currently, bisulfite conversion combined with next-generation sequencing represents the most widely used strategy for analyzing DNA methylation. Table 1 summarizes the major methylation-detection approaches, including their principles, advantages, limitations, and potential applications in transplantation research. Continued advances in DNA methylation detection technologies expand the technical toolkit for epigenetic research and support the development of novel epigenetic therapeutic strategies41,42,43,44,45.

2. Methylation characteristics of early thymic cell development and differentiation

Transplant rejection involves complex mechanisms that include both cell-mediated and antibody-mediated immune responses. Current evidence in transplant immunology indicates that T cell-mediated immunity plays a central role in graft rejection46,47. The thymus functions as the primary organ for T cell development, differentiation, and maturation48. During thymocyte development, the precursor stage of T cells, DNA methylation patterns undergo continuous and dynamic remodeling. These changes include both demethylation and methylation at genomic regions that regulate T cell transcription, although these processes do not occur in a fully balanced manner. During early development, genes encoding key T cell receptor (TCR) components and essential regulatory factors, including CD3, RUNX3, RORC, RAG1, and LCK, predominantly undergo demethylation7. More broadly, DNA demethylation occurs more frequently than methylation during immune cell differentiation49,50. In contrast, de novo methylation is relatively limited and mainly occurs during the early commitment stage of thymocyte development7. De novo methylation is also critical for silencing genes associated with the pluripotent potential of stem cells, thereby enabling lineage commitment and differentiation7,51. Another important feature of thymocyte DNA methylation is that most methylation changes remain stable and largely irreversible once established during differentiation. However, some genes, such as the RAG genes, display dynamic regulation: they undergo demethylation during early immune cell development and are subsequently remethylated at later stages7.

3. DNA methylation in immune cell differentiation and function

DNA methylation plays a crucial role in regulating the differentiation, function, and plasticity of diverse immune cell populations, thereby influencing the outcome of transplant immune responses.

  1. Adaptive immune cells
    1. Helper T cells (CD4+ T Cells)
      CD4+ T cells act as the primary effector cells in acute organ transplant rejection52,53. Naive T cells (Tn) differentiate into multiple CD4+ T cell subsets through coordinated genetic, epigenetic, and additional regulatory mechanisms. Upon stimulation by specific signals, the epigenetic landscape of naive T cells can change, thereby altering gene transcription and expression. These changes can ultimately influence both the type and intensity of immune rejection following transplantation. After T cell activation, the IL2 gene undergoes rapid demethylation and remains in an unmethylated state. This epigenetic change is essential for enhancing the transcription and expression of genes that support T cell function54.
      DNA methylation also plays a critical role in directing the differentiation of naive T cells into Th1 and Th2 subsets55,56. In naive CD4+ T cells, the IFNG gene is highly methylated; it becomes demethylated specifically during Th1 differentiation, while remaining heavily methylated in Th2 cells57. In contrast, the IL4 gene is strongly methylated in naive T cells and Th1 cells but undergoes partial demethylation in Th2 cells58. External factors can further regulate these methylation patterns by modulating the activity of DNA methyltransferases (DNMTs). For example, vitamin D deficiency increases DNMT activity and promotes hypermethylation of the IFNG gene, whereas vitamin D supplementation can reverse these changes59. Biological aging also influences DNA methylation patterns. Studies, including those by Yu, show that DNMT3a mRNA expression and methylation of the IL4 gene promoter increase with age, whereas methylation of the IFNG gene promoter decreases60. These findings suggest that age-related changes in DNA methylation may shift the balance between Th1 and Th2 cell responses.
      The differentiation of naive T cells also involves two other important CD4+ T cell subsets: Th17 and regulatory T (Treg) cells61,62. DNA methylation tightly regulates this process. The expression of the Th17-specific transcription factor RORγt and the cytokine IL-17 depends on the methylation status of their respective gene promoter regions63,64,65. Th17 cells within graft tissues can aggravate transplant rejection and promote vascular injury66. DNA methylation also influences the functional plasticity of Th17 cells. Under conditions of chronic inflammation, the IFNG gene in Th17 cells remains demethylated, allowing these cells to produce IFN-γ. As a result, Th17 cells can acquire features of both Th1 and Th17 phenotypes67. Moreover, in vitro studies show that specific stimulation conditions can drive Th17 cells to differentiate into functional Treg cells with strong immunosuppressive activity68.
      In contrast, Treg cells play a critical role in maintaining immune tolerance and preserving homeostasis within grafts69. These cells can originate in the thymus or differentiate in the periphery under the influence of TGF-β; regardless of their origin, Treg cells consistently express the transcription factor Foxp370. Epigenetic regulation, particularly DNA methylation, plays a key role in controlling the expression of genes associated with Treg function, including Foxp3 and Ctla4, thereby directly influencing their transcriptional activity71,72,73,74. During thymic Treg cell development, the Foxp3 gene undergoes progressive demethylation. This demethylated state persists after the cells migrate to peripheral tissues and requires sustained TCR signaling of appropriate strength62,75,76,77. In the absence of DNMT1, TCR stimulation can effectively induce Foxp3 expression in Foxp3-negative T cells in both the thymus and peripheral tissues. However, if TCR stimulation fails to induce sufficient epigenetic remodeling, cells cannot maintain stable Foxp3 expression, which is essential for preserving the Treg phenotype62,75,78. Stable expression of Foxp3 is largely controlled by epigenetic modifications at cis-regulatory elements, particularly conserved non-coding sequences (CNS)71,79,80. Among these, the methylation status of the Treg-specific demethylated region (TSDR) serves as a reliable marker for distinguishing stable from unstable Treg populations71,81,82,83,84,85,86. In naturally occurring naive Treg cells (nTregs), the TSDR remains unmethylated, allowing the recruitment of transcription factors such as Stat5, NFAT, Runx1, and CREB, which support stable Foxp3 expression. In contrast, in induced Treg cells (iTregs), the TSDR is typically methylated, leading to less stable Foxp3 expression72,74,87,88,89. In addition, loss of demethylation enzymes such as TET1 or TET2 leads to hypermethylation of the Foxp3 locus, which impairs Treg function and promotes the development of autoimmune diseases90. Clinical studies further demonstrate that higher levels of Foxp3 demethylation in renal allograft biopsy samples with subclinical rejection are associated with improved graft outcomes82,84.
      Treg cells have increasingly been investigated as a means of preventing allograft rejection and promoting immune tolerance91. A sufficient number of Treg cells must persist within the graft to effectively suppress effector T cells that drive transplant rejection, thereby maintaining immune tolerance92. However, Treg cells exhibit a degree of phenotypic instability. Under certain conditions, they can undergo epigenetic changes, including demethylation of the RORC gene, which leads to expression of the pro-inflammatory cytokine IL-1793,94. This shift highlights the plasticity of Treg cells and poses a challenge for their therapeutic use. Experimental studies further suggest that epigenetic modulation can enhance Treg function. For example, Guo et al. showed in animal models that combining DNA methylation inhibitors with IL-35 increases Foxp3 expression, promotes Treg cell differentiation, and improves graft survival95. Despite these advances, the understanding of Treg cell-related mechanisms remains incomplete. Future studies should define the conditions that promote Treg differentiation and stabilize the Treg phenotype, with the goal of applying these findings to the treatment of immune-mediated diseases.
    2. Cytotoxic T cells (CD8+ T Cells)
      After activation, naive CD8+ T cells differentiate into cytotoxic effector cells known as cytotoxic T lymphocytes (CTLs). These cells are commonly classified into two subsets: Tc1 cells, which produce IFN-γ, and Tc2 cells, which produce IL-4 and IL-596. Clinical studies show that the proportion of CD69+/CD8+ T cells in the peripheral blood of heart transplant patients correlates with severe rejection. In addition, CD8+ T cells within myocardial tissue display a CD69+ activated phenotype and exhibit perforin-mediated cytotoxic activity97,98. Experimental evidence further supports the role of CD8+ T cells in transplant rejection. Jones et al. demonstrated that, in T cell-depleted mice generated through thymectomy and anti-CD4/CD8 treatment, transfer of TCR antigen-specific CD8+ T cells alone is sufficient to induce rejection of fully mismatched allogeneic heart grafts99. These findings highlight the critical contribution of CD8+ T cells to immune-mediated graft rejection. DNA methylation also regulates CD8+ T cell development and function. In the absence of DNMT1, thymocyte survival is impaired100. In addition, deletion of DNMT3a in mature CD8+ T cells promotes memory cell differentiation while reducing terminal effector differentiation. This effect is partly mediated by increased expression of T cell factor 1 (Tcf1), as DNMT3a targets the promoter region of the Tcf7 gene and induces de novo methylation in early effector CD8+ T cells101. Furthermore, in a mouse model of acute viral infection, conditional deletion of TET2 in T cells enhances the formation of memory CD8+ T cells102. Together, these findings demonstrate that DNA methylation critically regulates the development, differentiation, and functional responses of CD8+ T cells.
    3. B cells
      T cells play a central role in transplant rejection; however, B cells also contribute to both cellular and humoral rejection responses103,104. Humoral rejection is primarily mediated by B lymphocytes. Upon activation, B cells differentiate into plasma cells that produce and secrete large amounts of specific antibodies, which can trigger inflammatory damage in the graft105. DNA methylation further regulates B-cell immune responses. Lee et al. showed that extensive DNA demethylation occurs during early B cell development, particularly within gene body regions and non-CpG island regions. In contrast, the regulatory influence of DNA methylation becomes less pronounced at later stages of B cell maturation106. In addition, Shaknovich et al. identified significant differences in DNA methylation profiles between germinal center B cells and naive B cells107. Germinal center B cells undergo demethylation, which alters the expression of functional genes and affects key signaling pathways, including NF-κB and MAPK pathways107,108. Functional studies further demonstrate that DNA methylation constrains B-cell activity. Deletion of the de novo methyltransferases Dnmt3a and Dnmt3b (Dnmt3 deficiency) promotes B cell development and maturation. At the same time, it enhances B-cell activation and supports the expansion of germinal center B cells and plasma cells. These findings indicate that de novo DNA methylation normally acts to limit B cell activation and restrain plasma cell differentiation109.
  2. Innate immune cells
    The immune response following solid organ transplantation involves coordinated interactions between innate and adaptive immunity. The innate immune system includes hematopoietic and non-hematopoietic cells such as dendritic cells, macrophages, natural killer cells, and neutrophils, all of which can contribute to post-transplant immune rejection110.
    Dendritic cells act as key regulators that bridge innate and adaptive immunity, with the capacity to promote either immune activation or tolerance111,112. During differentiation from monocytes, dendritic cells undergo widespread changes in DNA methylation, characterized by a marked reduction in methylation levels across many genomic regions. These changes occur primarily at enhancer regions and transcription factor-binding sites that are essential for lineage specification and immune activation113,114,115. A hallmark of this differentiation process is the downregulation of CD14 and upregulation of CD209 on the cell surface. This shift correlates with demethylation of CpG sites within the promoter region of the CD209 gene116. In addition, treatment with DNA methylation inhibitors significantly increases the expression of co-stimulatory molecules such as CD40 and CD86, thereby enhancing antigen presentation and promoting the functional maturation of dendritic cells. These findings indicate that DNA methylation directly regulates dendritic cell function and immune activity117.
    Monocytes and macrophages are essential components of the immune system because they mediate the phagocytosis and clearance of abnormal cells and invading pathogens. Extensive evidence shows that macrophages contribute not only to the inflammatory damage observed in early acute transplant rejection but also to the progression of fibrosis during late chronic rejection118,119. The balance between M1 macrophages (classically activated) and M2 macrophages (alternatively activated) critically regulates immune responses. A shift toward M1 macrophage dominance promotes inflammation and tissue injury. In contrast, reducing DNMT1 expression, either through DNA methylation inhibitors or gene knockout, lowers methylation at the peroxisome proliferator-activated receptor γ1 (PPARγ1) promoter. This change promotes M2 macrophage activation and helps limit immune-mediated damage120. Differences in DNA methylation patterns further highlight the role of epigenetic regulation in macrophage function. Studies have identified significant variation in promoter methylation of specific genes in peripheral blood monocytes/macrophages between individuals with and without coronary artery disease121. In addition, differentiation of monocytes into macrophages involves substantial changes in methylation at transcription factor-binding sites, indicating that DNA methylation in key regulatory regions plays a precise and critical role in macrophage differentiation122.
    Natural killer (NK) cells exert both effector and regulatory functions in transplant rejection. They can promote graft rejection while also contributing to the development of immune tolerance. During the differentiation of bone marrow hematopoietic stem cells into NK cells, reduced methylation of the KIR gene leads to increased KIR expression, which plays an important role in immune regulation. In addition, treatment with DNA methylation inhibitors induces demethylation of the KIR gene and promotes its expression in NK cells123,124. These findings indicate that DNA methylation is a key regulator of NK cell function.
    Neutrophils also participate actively in transplant rejection. Activated neutrophils release a range of mediators that recruit and activate antigen-presenting cells, thereby initiating antigen-specific T cell responses and amplifying immune rejection125,126,127. PRV-1, an anchor protein expressed on neutrophils, is regulated by DNA methylation at its promoter region under both physiological and pathological conditions128.

4. DNA methylation in key signaling pathways

DNA methylation not only directly regulates the transcription of functional genes but also influences cellular behavior by modulating key signaling pathways. For example, hypermethylation of the promoter region of the secreted frizzled-related protein (SFRP) gene leads to gene silencing. This silencing disrupts normal regulation of the Wnt/β-catenin signaling pathway, resulting in its aberrant activation and promoting the development of colorectal cancer129. Similarly, hypermethylation of upstream negative regulators of the mTOR signaling pathway in immune cells reduces their expression, leading to excessive mTOR activation and contributing to inflammatory injury in diabetic kidneys. Interventions such as decitabine or RNA interference can reduce methylation of these regulatory genes by inhibiting DNMT1, thereby attenuating the progression of diabetic nephropathy130. In addition, DNA methyltransferase inhibitors can suppress cell proliferation by regulating signaling pathways such as NF-κB and JAK/STAT, thereby influencing disease development and progression131,132 (Figure 1).

5. Clinical implications: immunosuppressive drugs and DNA methylation interactions

Standard-of-care immunosuppressive agents have been shown to influence DNA methylation patterns in immune cells, although the effects vary across different drugs and genomic contexts. Studies of IFNγ promoter methylation in T cells demonstrated that mycophenolic acid counteracts demethylation induced by T cell activation, whereas tacrolimus does not exert the same effect at this specific locus133. In contrast, sirolimus has been shown to modulate global methylation profiles through its effects on mTOR signaling pathways134, and DNA methylation itself has been demonstrated to regulate the mTOR pathway, thereby affecting allograft survival and acute rejection after renal transplantation135. Furthermore, glucocorticoids such as dexamethasone induce widespread DNA methylation remodeling within the peripheral immune compartment. The neutrophil dexamethasone methylation index serves as a sensitive pharmacodynamic marker of glucocorticoid exposure and is associated with immunosuppressive immune profiles136. ATG induction therapy has also been reported to alter the DNA methylome of kidney transplant recipients, and methylation-based models have been shown to predict infection risk more effectively than transcriptomic profiles137. Individual epigenetic variability may influence patient responses to these therapies, suggesting that methylation biomarkers could potentially guide personalized immunosuppressive regimens136,137. These drug–epigenome interactions warrant further investigation because they may have significant implications for optimizing long-term graft outcomes.

6. Challenges and perspectives: Balancing epigenetic modulation with immune safety

Despite their promise in transplantation, DNMT inhibitors (DNMTis), such as azacitidine and decitabine, pose infectious and oncogenic risks. Treatment with these agents has been associated with severe septic complications138,139, and systemic hypomethylating-agent exposure has also been associated with an increased risk of secondary acute myeloid leukemia transformation, with affected patients showing a median overall survival of less than 5 months140. Beyond drug-related toxicities, the lack of cell-type specificity represents an important challenge. Systemic demethylation may destabilize the Treg compartment while activating effector T cells, potentially exacerbating rejection141, and may compromise CD8+ memory T cell protection against opportunistic pathogens such as CMV101,102.

To overcome these limitations, emerging strategies aim to achieve cell-type- and locus-specific modulation. Nanoparticle platforms can deliver DNMT is preferentially to graft-infiltrating cells142,143. CRISPR/dCas9 epigenome editing enables targeted demethylation of Foxp3-TSDR to stabilize Tregs without global effects144,145. Biomarker-guided monitoring may also support safer clinical translation146.

Conclusions

Improving graft survival remains a primary goal in organ transplantation research. Transplant rejection is a complex immunological process in which epigenetic modifications from both the donor organ and the recipient interact dynamically to shape the overall epigenetic landscape. The recipient's immune system is a major driver of graft rejection. Epigenetic mechanisms critically regulate the development, differentiation, and function of immune cells, thereby influencing rejection responses and graft survival after transplantation. In addition, factors such as immunosuppressive drugs, infections, and the post-transplant environment further complicate the relationship between epigenetic regulation and immune responses. These factors can alter epigenetic patterns and modify immune cell behavior, adding another layer of complexity to transplant outcomes. Further investigation of the relationship between epigenetic mechanisms and transplant rejection is therefore needed to identify novel biomarkers and therapeutic targets and to improve diagnostic approaches and treatment strategies in organ transplantation.

Immune cell signaling dysregulation diagram; TET/DNMT impact on immunological balance and graft function.
Figure 1. DNA methylation in transplant immunity. Immune cells maintain distinct intrinsic DNA methylation patterns throughout their lifespan. Disruption of this physiological process can induce aberrant DNA methylation and dysregulation of downstream signaling pathways, ultimately resulting in impaired immune homeostasis and allograft dysfunction.Please click here to view a larger version of this figure.

MethodPrincipleAdvantagesLimitationsApplications in Transplantation
MeDIP-seq⁴¹Anti-5mC antibody enrichment + NGSCost-effective for genome-wide analysis; suitable for large sample cohortsLow resolution (~100–300 bp); cannot distinguish 5mC from 5hmCScreening of global methylation changes in PBMCs from transplant recipients
WGBS⁴²Bisulfite conversion + NGSSingle-base resolution; genome-wide coverageHigh cost; requires large data volumeComprehensive methylome mapping of graft biopsies; identification of novel rejection-related DMRs
RRBS⁴³Restriction enzyme enrichment + bisulfite conversion + NGSCost-effective; high coverage of CpG-rich regionsLimited coverage of non-CpG and CpG-poor regionsTargeted methylome analysis in graft tissue with reduced sequencing cost
Methylation-specific PCR⁴⁴Bisulfite conversion + PCR with methylation-specific primersHigh sensitivity; simple, rapid, and low costTargets only specific loci; qualitative or limited quantitative analysisValidation of candidate DMRs from discovery cohorts; clinical biomarker development
Pyrosequencing⁴⁵Bisulfite conversion + sequencing-by-synthesisQuantitative; single-base resolution at targeted lociModerate throughput; requires prior target identificationPrecise quantification of methylation levels at specific CpG sites, such as FOXP3 TSDR in Treg cells

Table 1: Summary of major DNA methylation detection approaches. The table summarizes commonly used DNA methylation detection methods, their principles, advantages, limitations, and potential applications in transplantation research.

Disclosures

The authors declare no competing interests or potential conflicts of interest.

Acknowledgements

The authors thank Figdraw for assistance with figure preparation.

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