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Editorials and Perspectives: Overview

Epigenetics: Time to Translate Into Transplantation

McCaughan, Jennifer A.1,3; McKnight, Amy Jayne2; Courtney, Aisling E.1; Maxwell, Alexander P.1

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doi: 10.1097/TP.0b013e31824db9bd
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Epigenetics is the study of potentially heritable changes in gene expression without alteration of the nucleotide sequence. Epigenetic modifications exert their effects at the level of transcription or translation (Fig. 1). These epigenetic phenomena are dynamic and potentially modifiable, making them attractive therapeutic targets (1–3). Technological advances have enabled cost-effective, population-based epigenome-wide association studies to be conducted (Fig. 2), and online epigenetics resources have been created to aid researchers. These include the International Human Epigenome Consortium (, the National Institute for Health RoadMap Epigenomics Project (, and the Human Epigenome Atlas (

Epigenetic targets for transplantation from the genome to the phenome.
The evolution of epigenetics for renal transplantation.

Several clinical risk factors are known to adversely impact transplant outcomes, including donor age, organ ischemic times, recipient comorbidity, degree of human leukocyte antigen mismatch, and immunologic and nonimmunologic gene polymorphisms (4–8). Chronic allograft dysfunction results from both immunologic and nonimmunologic insults, and efforts to minimize these should abrogate ongoing graft injury. This model fails to consider the epigenetic effects of environmental stressors, which can persist long after the removal of the injurious process. Transplant recipients have typically experienced significant chronic illness, and it is conceivable that their epigenomes have been altered by the pathologic cellular milieu or drugs prescribed during periods of ill health. Understanding the contribution of epigenetics is one of the fundamental components of the “omics” approach to complex disease analysis (Fig. 1). Epigenetic modifications and genetic variation can act independently to influence gene expression but may also contribute synergistically to regulate gene expression. Integrating genetic and epigenetic datasets can provide powerful tools to identify risk factors for complex disease (9, 10), and this integration of biologic data could improve clinical risk prediction for long-term transplantation outcomes.

The concept of inducible and heritable phenotypic modification was first proposed by Lamarck (11)in 1809 when he hypothesized that organisms undergo physiologic changes in response to environmental stimuli that persist after cell division. More recently, evidence to support this Lamarckian view of inheritance has emerged from studies of individuals experiencing intrauterine malnutrition (12). Follow-up of children born after the Dutch winter hunger famine of 1944 to 1945 confirmed they had a higher body mass index and increased risk of diabetes and cardiovascular events in adulthood compared with their unexposed siblings; these complex disease phenotypes have persisted in their descendants (13). Epigenetic modifications are an important mechanistic link between remote environmental stress and longer term changes to the program of gene expression.


Major epigenetic mechanisms that impact gene expression include DNA methylation, histone modifications, and RNA interference. Experiments to address the effect of such modifications on transplantation outcomes are still in the early stages, but recent technological advances have enhanced the ability to generate robust and reproducible epigenetic data.

DNA Methylation

DNA methylation is an important mechanism that can silence or repress gene expression. DNA methylation is critical for fine control of multiple cellular functions, including differentiation, genomic imprinting, and X chromosome inactivation (14, 15). DNA methylation primarily involves the covalent binding of a methyl group to the cytosine pyrimidine ring in cytosine-phosphate diester-guanine (CpG) islands (16). CpG islands are high-density clusters of CpG dinucleotides; these are associated with gene promoters and are conserved across species (2, 17, 18). Methylation of CpG islands inhibits gene expression by directly impeding the binding of transcription factors (1, 19–22) or by attracting methyl CpG-binding proteins and histone-modifying enzymes, resulting in the formation of condensed chromatin (2, 18, 19).

Methylation-sensitive restriction endonucleases distinguish between methylated and unmethylated CpG islands, and the density of DNA methylation can be measured by immunoprecipitation. However, these do not provide information about the methylation status of specific CpG dinucleotides (2, 15, 23). Bisulfite treatment induces deamination of unmethylated cytosine to uracil with preservation of methylated cytosine. These methylated cytosine sites can subsequently be analyzed by mass spectrometry or DNA sequencing (1, 2, 23). Commercial arrays have recently been developed that facilitate analysis of the entire methylome (23).

Histone Modification

Histone proteins are essential to chromatin structure. There are multiple epigenetic modifications that can occur within the amino acid tails of histones 2a, 2b, 3, and 4. These affect the affinity of the histone molecules for DNA, thereby altering the structure of chromatin and determining the accessibility of DNA to transcription factors (15, 20). Histone modifications include acetylation, phosphorylation, methylation, and ubiquitination (17). Acetylation typically results in transcriptional activation, whereas the effects of the other modifications are variable and depend on the site of action of acetyltransferases, histone deacetylases (HDAC), and histone methylases (17).

Chromatin immunoprecipitation is used to quantify histone modifications. Chromatin is precipitated using antibodies to specific histone modifications and the affected DNA region analyzed by microarray or sequencing (1, 24).

RNA Interference

RNA can reduce gene expression after transcription by repressing translation of messenger RNA (mRNA) or increasing mRNA degradation (25, 26). Advances in transcriptomic profiling have revealed relatively large numbers of noncoding RNA sequences transcribed from the human genome; micro-RNA (miRNA) form part of this group. These small, noncoding RNA molecules can regulate gene expression and epigenetic phenomena, resulting in changes in levels of thousands of proteins. Sequencing, microarrays, or quantitative real-time polymerase chain reaction may be used to analyze miRNA.

The discovery and continued characterization of miRNAs, RNA molecules composed of approximately 22 nucleotides (27), has revolutionized the understanding of gene regulation, cell differentiation, proliferation, and apoptosis. A complex epigenetic network exists whereby even miRNA expression is under epigenetic control (28). Several miRNAs have been associated with allograft rejection (29). Lorenzen et al. (30) recently reported alteration in miRNAs in the urine of renal transplant recipients with acute rejection, suggesting that miRNAs may prove to be useful noninvasive biomarkers in transplantation.


There is increasing evidence that epigenetic phenomena play a major role in chromosomal defects (31–33) and common complex diseases (1, 34, 35).

DNA methylation, histone modification, and RNA interference have been implicated in oncogenesis. Aberrant epigenetic control causes transcriptional silencing of tumor suppressor genes, activation of oncogenes, and increased chromosomal instability (14, 32, 36); recognition of this has led to diagnostic, prognostic, and therapeutic advances. Epigenetic biomarkers have been developed for gastrointestinal, breast, and prostate cancers (36–38). In hemato-oncology, demethylating agents have proven to be effective treatments (39, 40). The oncogenic phenotype of lung and breast cancer cells has been successfully modified by RNA interference in vitro, but this has not yet been translated into clinical practice (41).

Altered epigenomes have been demonstrated in chronic diseases, including cardiovascular disease, chronic obstructive pulmonary disease, depression, schizophrenia, chronic kidney disease (CKD), and obesity (1, 34, 35, 42–44). Prospective epigenetic studies are required to establish the causal role of these epigenetic modifications in complex disease.

CKD is associated with accumulation of uremic toxins and enhanced oxidative stress, and these have the potential to modify the epigenetic signature. In patients with CKD, global hypermethylation is independently associated with cardiovascular mortality (44). Recently, epigenetic hypermethylation of RASAL1, encoding an inhibitor of the Ras oncoprotein, has been reported to be associated with persistent fibroblast activation and renal fibrogenesis (45). This kidney fibrosis is ameliorated in animal models that are heterozygous for the gene encoding the methyltransferase enzyme DNMT1 (45). Both epigenetic modifications occurring in the recipient’s “uremic” environment and those resulting from allograft ischemia-reperfusion injury could potentially change gene expression and affect renal allograft outcomes.


The epigenetic signature of transplanted organs may be attributable to both the recipient and donor environments; the recipient epigenome has a broader role in the regulation of immune function (Table 1).

Role of epigenetics in cells involved in alloimmune rejection

Nonimmunologic Injury

The cumulative injurious burden of nonimmunologic insults contributes to the development of chronic allograft dysfunction. Recipients who receive a human leukocyte antigen–identical transplant can develop interstitial fibrosis as a result of nonimmunologic injury (46).

Prolonged ischemia preoperatively is associated with delayed graft function, acute rejection, chronic allograft dysfunction, and reduced transplant survival (47). Reperfusion of the ischemic graft stimulates the release of oxygen and hydroxyl free radicals, which damage DNA, proteins, lipids, and plasma membranes, and these free radicals have the potential to alter the epigenome. In a rodent model of renal transplantation, it was demonstrated that prolonged cold ischemia of rat kidneys caused hypomethylation of the complement factor 3 gene (48, 49). Loss of transcriptional repression of this gene provides a plausible explanation for the accentuated immunologic injury, which often follows protracted ischemia of the allograft. Of interest, myocardial hypoxia induces HDAC enzymes, but the area of experimental cardiac ischemic injury can be substantially reduced by treatment with HDAC inhibitors. These acetylase antagonists inhibit cell death and reduce vascular permeability in the injured myocardium (50). H3 acetylation follows acute renal ischemia in mice, with resulting activation of inflammatory genes, enhanced cytokine expression, and fibrosis (51). If these epigenetic modifications contribute to allograft dysfunction, there may be an opportunity for therapeutic pharmacologic intervention.

Mehta et al. (52) compared the promoter methylation status of the CALCA gene between renal transplant recipients and healthy controls. Promoter hypermethylation was increased in the transplanted group compared with healthy controls. CALCA promoter hypermethylation was greatest in recipients with acute tubular necrosis compared with those with acute rejection or normal graft function (52). The methylation status of CADM1 is an independent predictor of the risk of recurrence of hepatocellular carcinoma after liver transplantation (53). Methylation-based biomarkers may prove to be noninvasive diagnostic and prognostic tools in transplantation.

Epigenetic modifications may play a role in viral infection after transplantation. Epstein-Barr virus infection is the predominant risk factor for posttransplant lymphoproliferative disorder (54), and Epstein-Barr virus infection of B lymphocytes results in the expression of several viral genes (55). A small study of recipients with posttransplant lymphoproliferative disorder identified enhanced DNA methylation at the promoter regions of two genes in the majority of affected individuals (56). Cytomegalovirus (CMV) infection causes significant morbidity in solid organ transplant recipients (57). In vitro, CMV gene expression in infected cells can be silenced by DNA hypermethylation, and this gene silencing may be reversed by the addition of a DNA demethylase (58). Of further interest, the transition from acute to latent CMV infection is associated with histone modification in murine models (59). Recent evidence demonstrates that hepatocellular carcinoma secondary to hepatitis B infection exhibits specific DNA methylation profiles compared with liver cancers associated with hepatitis C virus, alcoholism, or aflatoxins (60). It is unclear whether these epigenetic modifications contribute to the development of hepatocellular carcinoma. The role of epigenetics in viral infections after transplantation is beginning to be explored and may both provide valuable insights into the pathogenesis of these infections and identify potential therapeutic targets.

Immunologic Injury

Allograft rejection is a complex process involving interaction between the donor cells of the transplanted organ and the recipient immune system. It remains a persistent challenge in transplantation. Although the incidence of acute rejection could be reduced by increasing the immunosuppressive load, this is at the expense of a predisposition to serious infection and malignancy. All of the major immune cells involved in allograft rejection are influenced by epigenetic factors (Table 1).

The major histocompatibility complex (MHC) encodes glycoproteins, which present antigens to the immune system. MHC class I antigens are present on almost all nucleated cells, whereas class II are selectively expressed by antigen-presenting cells. The initial phase of rejection is the recognition of an alloantigen by T cells (61, 62). Direct allorecognition relies on T-cell detection of an alloantigen presented by a donor cell. Donor dendritic cells have a key role; they reside in the allograft but migrate when activated by inflammatory cytokines to allow T-cell activation (63). The indirect pathway involves the presentation of alloantigens by self MHC molecules (64). Concurrent T-cell receptor and costimulatory signaling propagate proliferation and differentiation of the T-cell lineage, cytokine production, and T-cell migration to the inflammatory site (61, 65).

MHC expression is fundamental to alloantigen recognition. Downregulation of MHC expression is a characteristic of gametes, embryonic cells, and neoplastic cells and confers them a degree of protection from the immune system (21). DNA methylation controls MHC class I and II expression; MHC class II expression is also affected by histone modifications. The histone methyltransferase CARM1 is critical to the constitutive expression of MHC II in B cells, and acetylation of the MHC II promoter enhances gene expression (66). In acute rejection, there is an increase in MHC II glycoproteins within the allograft (67).

Epigenetic mechanisms control T-cell activation through the production of interleukin-2 (IL-2). In inactive T cells, the IL-2 promoter is methylated and packaged within condensed chromatin, making it inaccessible to transcription factors. Following simultaneous T-cell receptor and costimulatory signaling, DNA demethylation and chromatin remodeling allow upregulation of IL-2 (19). Histone deacetylation also determines T-cell activation; the HDAC inhibitor FR276457 prolongs graft survival in animal models of kidney and heart transplantation (68, 69). The costimulatory signal between dendritic cells and T cells has been successfully blocked by RNA interference in mice (70). This attenuated the T-cell response to alloantigens and prolonged allograft survival (70).

B lymphocytes also play a significant role in rejection because of the high affinity of the B-cell receptor for foreign antigens. After interaction with a complementary epitope, the B cell communicates with its cognate T cell. Direct signaling and T-cell cytokine production stimulate the maturation, activation, and differentiation of B cells into plasma cells and memory cells (71). Alloantibodies cause severe graft rejection by binding to the transplanted organ and initiating the inflammatory cascade (72). A role for epigenetic regulation of B cells has recently been discovered. DNA methylation, histone modification, and chromatin remodeling determine B-cell receptor commitment, phenotypic stability, and cell signaling, whereas miRNAs have been implicated in differentiation (73).

T regulatory cells (Tregs) are of fundamental importance in immune modulation and the maintenance of self-tolerance. Their main role is to suppress self-reactive T cells that have escaped negative selection in the thymus, but Tregs also attenuate allograft rejection (74, 75). Several studies have identified an association between chronic rejection and low Treg populations (76, 77).

Although epigenetic modifications are important in many immune cells, they are essential to the stability and function of the suppressive Tregs. FOXP3 is a transcription factor that is constitutively expressed by Tregs and has a crucial role in the modulation of the immune system and the maintenance of self-tolerance (78–81). Stable FOXP3 expression is unique to Tregs and depends on the hypomethylation of the Treg-specific demethylating region (Fig. 3) (79, 80). Exposure of T cells to demethylases and HDAC inhibitors in vitro enhances FOXP3 expression, increases the Treg population, and augments suppressive function (18, 80, 82). Demethylating agents have been used to induce tolerance in graft versus host disease. They attenuate the disease course by enhancing FOXP3 expression (40). FOXP3 itself acts as a transcriptional repressor by inducing histone deacetylation of the promoter regions of pivotal cytokine genes (83).

TheFOXP3 gene at chromosome Xp11.23.


Epigenetic modifications influence many of the processes implicated in acute and chronic allograft dysfunction. The challenge is to modify the epigenome for therapeutic benefit. This has already been achieved in oncology where demethylating agents form part of the armamentarium used to treat hematologic malignancies (39, 40) and may also have a role in solid organ neoplasia (84, 85).

Genetic variation may have a significant effect on the action of immunosuppressants. Thiopurine methyltransferase genotyping can be used in clinical practice to assess the risk of myelosuppression with azathioprine treatment (86), and mutations in the multidrug resistance 1 gene can also affect clinical response to azathioprine (87). Calcineurin inhibitors are metabolized by cytochrome P450 enzymes, and an association has been identified between the CYP3A5 genotype and tacrolimus dosing requirements (88). Mycophenolate mofetil action and the incidence of adverse events are affected by single-nucleotide polymorphisms in the inosine monophosphate dehydrogenase type I and II genes (89, 90), the solute carrier organic anion transporter family member 1B1 gene (91), the IL-12A gene, complement factor H gene, and the cytochrome P450 2C8 gene (92). It is likely that immunosuppressive regimens induce clinically significant epigenetic modification. Glucocorticoids inhibit natural killer cell activity in vitro by altering histone deacetylation, but their global effect on the epigenome is unknown (93). The epigenetic effects of other immunosuppressive agents still remain to be elucidated. A greater understanding of the epigenetic modifications involved in allograft rejection could lead to the development of pharmacologic agents that act selectively on epigenetic targets.

There is also potential for epigenetic therapies to maintain the integrity of the epigenome of the transplanted organ. DNA methylating agents could prevent the aberrant demethylation of gene promoters that occurs during the cold ischemic period and reduce the subsequent inflammatory response.

The major disadvantages of current epigenetic therapies are the lack of specificity and unknown long-term safety profiles. Demethylases and HDAC inhibitors induce epigenome-wide changes; this is associated with chromosomal instability, a feature of neoplastic cells (32). Although this may be an acceptable risk in individuals with life-threatening malignancy, it would be more difficult to justify exposing other patients to these drugs. Transplant recipients already have an increased cancer predisposition as a consequence of immunosuppressive therapy. The risk:benefit ratio for current epigenetic therapies in transplant recipients is unknown.

The nonspecific nature of epigenetic treatments could be overcome by harnessing RNA interference. These RNA molecules are specific to target mRNA, and this is an area of rapid development (29). Several promising miRNA therapies are undergoing preclinical testing, but there has not yet been a translation of miRNA therapy from bench to bedside.


Epigenetic modification plays a key role in biologic processes that contribute to allograft dysfunction. Detailed interrogation of the epigenome in transplant recipients and donors will provide further insight into the epigenetic modifications associated with allograft survival. Epigenetic research is a hot topic, which is rapidly generating data that not only improve understanding of biologic mechanisms but also offer scope for prognostic and therapeutic clinical utility in the short to medium term.


1. Dwivedi RS, Herman JG, McCaffrey TA, et al.. Beyond genetics: Epigenetic code in chronic kidney disease. Kidney Int 2010; 79: 23.
2. Callinan PA, Feinberg AP. The emerging science of epigenomics. Hum Mol Genet 2006; 15: R95.
3. Fraga MF, Ballestar E, Paz MF, et al.. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005; 102: 10604.
4. Sterling WA, Aldrete JS, Cobbs CG, et al.. Treatment of end-stage renal disease by transplantation: Clinical results with 111 cases. Am Surg 1975; 41: 4.
5. Courtney AE, McNamee PT, Maxwell AP. The evolution of renal transplantation in clinical practice: For better, for worse? QJM 2008; 101: 967.
6. Moore J, McKnight AJ, Simmonds MJ, et al.. Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure. JAMA 2010; 303: 1282.
7. Morgun A, Shulzhenko N, Rampim GF, et al.. Interleukin-2 gene polymorphism is associated with renal but not cardiac transplant outcome. Transplant Proc 2003; 35: 1344.
8. Thakkinstian A, Dmitrienko S, Gerbase-Delima M, et al.. Association between cytokine gene polymorphisms and outcomes in renal transplantation: A meta-analysis of individual patient data. Nephrol Dial Transplant 2008; 23: 3017.
9. Bell CG, Finer S, Lindgren CM, et al.. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS One 2010; 5: e14040.
10. Shen L, Toyota M, Kondo Y, et al.. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci USA 2007; 104: 18654.
11. Lamarck JBP, AdCdM. Philosophie zoologique: Ou Exposition des considaerations relative a´a l’histoire naturelle des animaux. Paris: Dentu et L’Auteur; 1809.
12. Heijmans BT, Tobi EW, Lumey LH, et al.. The epigenome: Archive of the prenatal environment. Epigenetics 2009; 4: 526.
13. Roseboom TJ, van der Meulen JH, Osmond C, et al.. Coronary heart disease after prenatal exposure to the Dutch famine, 1944–45. Heart 2000; 84: 595.
14. Okano M, Bell DW, Haber DA, et al.. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999; 99: 247.
15. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell 2007; 128: 669.
16. Ramsahoye BH, Biniszkiewicz D, Lyko F, et al.. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci USA 2000; 97: 5237.
17. Handel AE, Ebers GC, Ramagopalan SV. Epigenetics: Molecular mechanisms and implications for disease. Trends Mol Med 2010; 16: 7.
18. Tao R, de Zoeten EF, Ozkaynak E, et al.. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 2007; 13: 1299.
19. Fitzpatrick DR, Wilson CB. Methylation and demethylation in the regulation of genes, cells, and responses in the immune system. Clin Immunol 2003; 109: 37.
20. Hagmann CA, Schildberg FA, Tolba RH. Epigenetics and transplantation: Clinical applications of chromatin regulation. Discov Med 2010; 10: 511.
21. van den Elsen PJ, Holling TM, van der Stoep N, et al.. DNA methylation and expression of major histocompatibility complex class I and class II transactivator genes in human developmental tumor cells and in T cell malignancies. Clin Immunol 2003; 109: 46.
22. Lippman Z, Martienssen R. The role of RNA interference in heterochromatic silencing. Nature 2004; 431: 364.
23. Gupta R, Nagarajan A, Wajapeyee N. Advances in genome-wide DNA methylation analysis. Biotechniques 2010; 49: 3.
24. Naesens M, Sarwal MM. Molecular diagnostics in transplantation. Nat Rev Nephrol 2010; 6: 614.
25. Lodish HF, Zhou B, Liu G, et al.. Micromanagement of the immune system by microRNAs. Nat Rev Immunol 2008; 8: 120.
26. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet 2008; 9: 102.
27. Kozomara A, Griffiths-Jones S. miRBase: Integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 2011; 39: D152.
28. Sato F, Tsuchiya S, Meltzer SJ, et al.. MicroRNAs and epigenetics. FEBS J 2011; 278: 1598.
29. Shan J, Feng L, Luo L, et al.. MicroRNAs: Potential biomarker in organ transplantation. Transpl Immunol 2011; 24: 210.
30. Lorenzen JM, Volkmann I, Fiedler J, et al.. Urinary miR-210 as a mediator of acute T-cell mediated rejection in renal allograft recipients. Am J Transplant 2011; 11: 2221.
31. Amor DJ, Halliday J. A review of known imprinting syndromes and their association with assisted reproduction technologies. Hum Reprod 2008; 23: 2826.
32. Eden A, Gaudet F, Waghmare A, et al.. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 2003; 300: 455.
33. Jin B, Tao Q, Peng J, et al.. DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 2008; 17: 690.
34. Gerken T, Girard CA, Tung YC, et al.. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 2007; 318: 1469.
35. Adcock IM, Ito K, Barnes PJ. Histone deacetylation: An important mechanism in inflammatory lung diseases. COPD 2005; 2: 445.
36. Phe V, Cussenot O, Roupret M. Methylated genes as potential biomarkers in prostate cancer. BJU Int 2010; 105: 1364.
37. Napieralski R, Brunner N, Mengele K, et al.. Emerging biomarkers in breast cancer care. Biomark Med 2010; 4: 505.
38. Corvalan AH, Maturana MJ. Recent patents of DNA methylation biomarkers in gastrointestinal oncology. Recent Pat DNA Gene Seq 2010; 4: 202.
39. Costa R, Abdulhaq H, Haq B, et al.. Activity of azacitidine in chronic myelomonocytic leukemia. Cancer 2011; 117: 2690.
40. Choi J, Ritchey J, Prior JL, et al.. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 2010; 116: 129.
41. Suzuki M, Sunaga N, Shames DS, et al.. RNA interference-mediated knockdown of DNA methyltransferase 1 leads to promoter demethylation and gene re-expression in human lung and breast cancer cells. Cancer Res 2004; 64: 3137.
42. Schroeder M, Krebs MO, Bleich S, et al.. Epigenetics and depression: Current challenges and new therapeutic options. Curr Opin Psychiatry 2010; 23: 588.
43. Gavin DP, Sharma RP. Histone modifications, DNA methylation, and schizophrenia. Neurosci Biobehav Rev 2010; 34: 882.
44. Stenvinkel P, Karimi M, Johansson S, et al.. Impact of inflammation on epigenetic DNA methylation—A novel risk factor for cardiovascular disease? J Intern Med 2007; 261: 488.
45. Bechtel W, McGoohan S, Zeisberg EM, et al.. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 2010; 16: 544.
46. Braun WE. Long-term results in 35 HLA-identical sibling and 3 HLA identical parent–child renal allograft recipients. Nephron 1978; 22: 232.
47. Moreira P, Sá H, Figueiredo A, et al.. Delayed renal graft function: Risk factors and impact on the outcome of transplantation. Transplant Proc 2011; 43: 100.
48. Parker MD, Chambers PA, Lodge JP, et al.. Ischemia-reperfusion injury and its influence on the epigenetic modification of the donor kidney genome. Transplantation 2008; 86: 1818.
49. Pratt JR, Parker MD, Affleck LJ, et al.. Ischemic epigenetics and the transplanted kidney. Transplant Proc 2006; 38: 3344.
50. Granger A, Abdullah I, Huebner F, et al.. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J 2008; 22: 3549.
51. Zager RA, Johnson AC, Becker K. Acute unilateral ischemic renal injury induces progressive renal inflammation, lipid accumulation, histone modification, and ‘end stage’ kidney disease. Am J Physiol Renal Physiol 2011; 301: F1334.
52. Mehta TK, Hoque MO, Ugarte R, et al.. Quantitative detection of promoter hypermethylation as a biomarker of acute kidney injury during transplantation. Transplant Proc 2006; 38: 3420.
53. Zhang W, Zhou L, Ding SM, et al.. Aberrant methylation of the CADM1 promoter is associated with poor prognosis in hepatocellular carcinoma treated with liver transplantation. Oncol Rep 2011; 25: 1053.
54. Nourse JP, Jones K, Gandhi MK. Epstein-Barr Virus-related post-transplant lymphoproliferative disorders: Pathogenetic insights for targeted therapy. Am J Transplant 2011; 11: 888.
55. Young LS, Dawson CW, Eliopoulos AG. The expression and function of Epstein-Barr virus encoded latent genes. Mol Pathol 2000; 53: 238.
56. Rossi D, Gaidano G, Gloghini A, et al.. Frequent aberrant promoter hypermethylation of O6-methylguanine-DNA methyltransferase and death-associated protein kinase genes in immunodeficiency-related lymphomas. Br J Haematol 2003; 123: 475.
57. Eid AJ, Razonable RR. New developments in the management of cytomegalovirus infection after solid organ transplantation. Drugs 2010; 70: 965.
58. Hsu CC, Li HP, Hung YH, et al.. Targeted methylation of CMV and E1A viral promoters. Biochem Biophys Res Commun 2010; 402: 228.
59. Liu XF, Yan S, Abecassis M, et al.. Establishment of murine cytomegalovirus latency in vivo is associated with changes in histone modifications and recruitment of transcriptional repressors to the major immediate-early promoter. J Virol 2008; 82: 10922.
60. Lambert MP, Paliwal A, Vaissière T, et al.. Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. J Hepatol 2011; 54: 705.
61. Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol 2010; 25: 61.
62. Batchelor JR, Lechler RI. Why MHC incompatible grafts induce strong primary alloimmunity. Transplant Proc 1982; 14: 535.
63. Kimber I, Cumberbatch M. Stimulation of Langerhans cell migration by tumor necrosis factor alpha (TNF-alpha). J Invest Dermatol 1992; 99: 48S.
64. Warrens AN, Lombardi G, Lechler RI. Presentation and recognition of major and minor histocompatibility antigens. Transpl Immunol 1994; 2: 103.
65. el-Sawy T, Fahmy NM, Fairchild RL. Chemokines: Directing leukocyte infiltration into allografts. Curr Opin Immunol 2002; 14: 562.
66. Wright KL, Ting JP. Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol 2006; 27: 405.
67. Barrett M, Milton AD, Barrett J, et al.. Needle biopsy evaluation of class II major histocompatibility complex antigen expression for the differential diagnosis of cyclosporine nephrotoxicity from kidney graft rejection. Transplantation 1987; 44: 223.
68. Kinugasa F, Nagatomi I, Nakanishi T, et al.. Effect of the immunosuppressant histone deacetylase inhibitor FR276457 in a canine renal transplant model. Transpl Immunol 2009; 21: 198.
69. Kinugasa F, Yamada T, Noto T, et al.. Effect of a new immunosuppressant histon deacetylase (HDAC) inhibitor FR276457 in a rat cardiac transplant model. Biol Pharm Bull 2008; 31: 1723.
70. Xiang J, Gu X, Qian S, et al.. Endoplasmic reticulum stress-mediated apoptosis involved in indirect recognition pathway blockade induces long-term heart allograft survival. J Biomed Biotechnol 2010; 2010: 705431.
71. Clatworthy MR. Targeting B cells and antibody in transplantation. Am J Transplant 2011; 11: 1359.
72. Smith KG, Clatworthy MR. Fc gamma RIIB in autoimmunity and infection: Evolutionary and therapeutic implications. Nat Rev Immunol 2010; 10: 328.
73. Parra M. Epigenetic events during B lymphocyte development. Epigenetics 2009; 4: 468.
74. Wolf M, Schimpl A, Hunig T. Control of T cell hyperactivation in IL-2-deficient mice by CD4(+)CD25(−) and CD4(+)CD25(+) T cells: Evidence for two distinct regulatory mechanisms. Eur J Immunol 2001; 31: 1637.
75. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004; 4: 665.
76. Louis S, Braudeau C, Giral M, et al.. Contrasting CD25hiCD4+T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation 2006; 81: 398.
77. Iwase H, Kobayashi T, Kodera Y, et al.. Clinical significance of regulatory T-cell-related gene expression in peripheral blood after renal transplantation. Transplantation 2011; 91: 191.
78. Li XC, Turka LA. An update on regulatory T cells in transplant tolerance and rejection. Nat Rev Nephrol 2010; 6: 577.
79. Huehn J, Polansky JK, Hamann A. Epigenetic control of FOXP3 expression: The key to a stable regulatory T-cell lineage? Nat Rev Immunol 2009; 9: 83.
80. Lal G, Bromberg JS. Epigenetic mechanisms of regulation of Foxp3 expression. Blood 2009; 114: 3727.
81. Floess S, Freyer J, Siewert C, et al.. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007; 5: e38.
82. van Loosdregt J, Vercoulen Y, Guichelaar T, et al.. Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 2010; 115: 965.
83. Chen C, Rowell EA, Thomas RM, et al.. Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J Biol Chem 2006; 281: 36828.
84. Iwata H, Sato H, Suzuki R, et al.. A demethylating agent enhances chemosensitivity to vinblastine in a xenograft model of renal cell carcinoma. Int J Oncol 2011; 38: 1653.
85. Mitmaker EJ, Griff NJ, Grogan RH, et al.. Modulation of matrix metalloproteinase activity in human thyroid cancer cell lines using demethylating agents and histone deacetylase inhibitors. Surgery 2011; 149: 504.
86. Anglicheau D, Legendre C, Thervet E. Pharmacogenetics in solid organ transplantation: Present knowledge and future perspectives. Transplantation 2004; 78: 311.
87. Mendoza JL, Urcelay E, Lana R, et al.. MDR1 polymorphisms and response to azathioprine therapy in patients with Crohn’s disease. Inflamm Bowel Dis 2007; 13: 585.
88. Kuypers DR, de Jonge H, Naesens M, et al.. A prospective, open-label, observational clinical cohort study of the association between delayed renal allograft function, tacrolimus exposure, and CYP3A5 genotype in adult recipients. Clin Ther 2010; 32: 2012.
89. Gensburger O, Van Schaik RH, Picard N, et al.. Polymorphisms in type I and II inosine monophosphate dehydrogenase genes and association with clinical outcome in patients on mycophenolate mofetil. Pharmacogenet Genomics 2010; 20: 537.
90. Kagaya H, Miura M, Saito M, et al.. Correlation of IMPDH1 gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation. Basic Clin Pharmacol Toxicol 2010; 107: 631.
91. Michelon H, König J, Durrbach A, et al.. SLCO1B1 genetic polymorphism influences mycophenolic acid tolerance in renal transplant recipients. Pharmacogenomics 2010; 11: 1703.
92. Jacobson PA, Schladt D, Oetting WS, et al.. Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation. Transplantation 2011; 91: 309.
93. Krukowski K, Eddy J, Kosik KL, et al.. Glucocorticoid dysregulation of natural killer cell function through epigenetic modification. Brain Behav Immun 2011; 25: 239.
94. Wright KL, Ting JP. Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol 2006; 27: 405.
95. Cuddapah S, Barski A, Zhao K. Epigenomics of T cell activation, differentiation, and memory. Curr Opin Immunol 2010; 22: 341.
96. Gold M, Hurwitz J, Anders M. The enzymatic methylation of RNA and DNA. Biochem Biophys Res Commun 1963; 11: 107.
97. Chalfie M, Horvitz HR, Sulston JE. Mutations that lead to reiterations in the cell lineages of C. elegans. Cell 1981; 24: 59.
98. Bird A, Taggart M, Frommer M, et al.. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 1985; 40: 91.
99. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843.
100. Pasquinelli AE, Reinhart BJ, Slack F, et al.. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000; 408: 86.
101. Zeng L, Kanwar YS, Amro N, et al.. Epigenetic and genetic analysis of p16 in dermal fibroblasts from type 1 diabetic patients with nephropathy. Kidney Int 2003; 63: 2094.
102. Sun Y, Koo S, White N, et al.. Development of a micro-array to detect human and mouse microRNAs and characterization of expression in human organs. Nucleic Acids Res 2004; 32: e188.
103. Sui W, Dai Y, Huang Y, et al.. Microarray analysis of MicroRNA expression in acute rejection after renal transplantation. Transpl Immunol 2008; 19: 81.
104. Rakyan VK, Down TA, Balding DJ, et al.. Epigenome-wide association studies for common human diseases. Nat Rev Genet 201; 12: 529.

Epigenetic; Histone; Methylation; miRNA; Transplant

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