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• W2256910130 abstract "Allograft outcome depends on a range of factors, including donor age, the allo-immune response, ischemia–reperfusion injury, and interstitial fibrosis of the allograft. Changes in the epigenome, and in DNA methylation in particular, have been implicated in each of these processes, in either the kidney or other organ systems. This review provides a primer for DNA methylation analyses and a discussion of the strengths and weaknesses of current studies, but it is also a perspective for future DNA methylation research in kidney transplantation. We present exciting prospects for leveraging DNA methylation analyses as a tool in kidney biology research, and as a diagnostic or prognostic marker for predicting allograft quality and success. Topics discussed include DNA methylation changes in aging and in response to hypoxia and oxidative stress upon ischemia–reperfusion injury. Moreover, emerging evidence suggests that DNA methylation contributes to organ fibrosis and that systemic DNA methylation alterations correlate with the rate of kidney function decline in patients with chronic kidney disease and end-stage renal failure. Monitoring or targeting the epigenome could therefore reveal novel therapeutic approaches in transplantation and open up paths to biomarker discovery and targeted therapy. Allograft outcome depends on a range of factors, including donor age, the allo-immune response, ischemia–reperfusion injury, and interstitial fibrosis of the allograft. Changes in the epigenome, and in DNA methylation in particular, have been implicated in each of these processes, in either the kidney or other organ systems. This review provides a primer for DNA methylation analyses and a discussion of the strengths and weaknesses of current studies, but it is also a perspective for future DNA methylation research in kidney transplantation. We present exciting prospects for leveraging DNA methylation analyses as a tool in kidney biology research, and as a diagnostic or prognostic marker for predicting allograft quality and success. Topics discussed include DNA methylation changes in aging and in response to hypoxia and oxidative stress upon ischemia–reperfusion injury. Moreover, emerging evidence suggests that DNA methylation contributes to organ fibrosis and that systemic DNA methylation alterations correlate with the rate of kidney function decline in patients with chronic kidney disease and end-stage renal failure. Monitoring or targeting the epigenome could therefore reveal novel therapeutic approaches in transplantation and open up paths to biomarker discovery and targeted therapy. Epigenetics involves the potentially stable and, ideally, inheritable mechanisms that control gene expression and that occur without changes in the DNA sequence (1.Petronis A. Epigenetics as a unifying principle in the aetiology of complex traits and diseases.Nature. 2010; 465: 721-727Crossref PubMed Scopus (514) Google Scholar). They can be generally grouped into three main categories: methylation of DNA, modifications of histones, and changes in the positioning of nucleosomes (2.Portela A Esteller M. Epigenetic modifications and human disease.Nature Biotechnol. 2010; 28: 1057-1068Crossref PubMed Scopus (2001) Google Scholar). The interactions between these different epigenetic modifications determine their effect on gene expression and are fundamental to the regulation of many cellular processes. Epigenetic changes are often triggered by developmental, environmental, or pathogenic stimuli and, because of their stability and heritability, can produce long-lasting cellular phenotypes (2.Portela A Esteller M. Epigenetic modifications and human disease.Nature Biotechnol. 2010; 28: 1057-1068Crossref PubMed Scopus (2001) Google Scholar). As such, they provide an interface between the environment and gene expression (1.Petronis A. Epigenetics as a unifying principle in the aetiology of complex traits and diseases.Nature. 2010; 465: 721-727Crossref PubMed Scopus (514) Google Scholar). In recent years, we have witnessed a growing interest in epigenetic research in various research domains, such as cancer or autoimmunity. Also, in the field of nephrology, interest has steadily been growing. However, so far, only few studies have focused on the role of epigenetic changes in kidney transplantation. This is somewhat surprising, as many key factors that influence DNA methylation, which is the best-characterized epigenetic mark, are of major prognostic significance in kidney transplantation. Indeed, advanced donor age, alloreactive immune responses, ischemia–reperfusion injury, and fibrosis significantly contribute to allograft survival and, at the same time, these factors also trigger DNA methylation changes. Therefore, this review aims to provide a perspective on the emerging role of DNA methylation in kidney transplantation. By pointing out major discoveries in related research fields, we aim to highlight how epigenetic research can provide novel insights into the mechanisms of kidney transplant failure and may thus contribute to improving long-term allograft survival. DNA methylation occurs almost exclusively at cytosines located in the context of a CpG dinucleotide (3.Schubeler D. Function and information content of DNA methylation.Nature. 2015; 517: 321-326Crossref PubMed Scopus (1265) Google Scholar). Although CpG dinucleotides are rare in the genome, a small fraction is clustered into “CpG islands.” CpG islands have a high CpG density, are unmethylated under normal conditions, and mostly colocalize with promoter regions in the genome (4.Bird AP. CpG-rich islands and the function of DNA methylation.Nature. 1986; 321: 209-213Crossref PubMed Scopus (3018) Google Scholar, 5.Rauch TA Wu X Zhong X A human B cell methylome at 100-base pair resolution.Proc Nati Acad Sci U S A. 2009; 106 (et al): 671-678Crossref PubMed Scopus (259) Google Scholar) (Figure 1). Methylation of CpG islands in promoters represses gene expression by displacing transcription factors and attracting methyl-binding proteins that trigger gene silencing (6.Fazzari MJ Greally JM. Epigenomics: beyond CpG islands.Nat Rev Genet. 2004; 5: 446-455Crossref PubMed Scopus (291) Google Scholar). DNA methylation leading to gene silencing is essential for dosage compensation in chromosome X-inactivation, for parent-of-origin–dependent imprinting, and more generally for cell differentiation and mammalian development (2.Portela A Esteller M. Epigenetic modifications and human disease.Nature Biotechnol. 2010; 28: 1057-1068Crossref PubMed Scopus (2001) Google Scholar) and has a major role in long-term gene expression silencing. In the CpG context, with methylation on both DNA strands mirroring each other, DNA methylation patterns can be faithfully copied on DNA replication and transmitted to both daughter cells. As a consequence, DNA methylation patterns are stable, unless when they are actively altered. Such alterations occur extensively during development, and DNA methylation patterns are therefore cell type and lineage specific. It thus endows unique functions to different cells and tissues that have identical genomes (7.Hon GC Rajagopal N Shen Y Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues.Nat Genet. 2013; 45 (et al): 1198-1206Crossref PubMed Scopus (331) Google Scholar, 8.Deaton AM Webb S Kerr AR Cell type-specific DNA methylation at intragenic CpG islands in the immune system.Genome Res. 2011; 21 (et al): 1074-1086Crossref PubMed Scopus (222) Google Scholar, 9.Illingworth RS, Gruenewald-Schneider U, De Sousa D, et al. Inter-individual variability contrasts with regional homogeneity in the human brain DNA methylome. Nucl Acids Res 2015.Google Scholar). For instance, the DNA methylome of the kidney closely resembles the DNA methylome of other mesoderm-derived tissues (7.Hon GC Rajagopal N Shen Y Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues.Nat Genet. 2013; 45 (et al): 1198-1206Crossref PubMed Scopus (331) Google Scholar). In addition, genes encoding kidney-specific transporters are hypomethylated in the rodent kidney compared with other organs (10.Kikuchi R Yagi S Kusuhara H Genome-wide analysis of epigenetic signatures for kidney-specific transporters.Kidney Int. 2010; 78 (et al): 569-577Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). When specifically focusing on rodent proximal tubular cells, again genes that were hypomethylated compared with the kidney in general included those that were essential for proximal tubular cellular function (11.Marumo T, Yagi S, Kawarazaki W, et al. Diabetes induces aberrant DNA methylation in the proximal tubules of the kidney. J Am Soc Nephrol 2015.Google Scholar). DNA methylation is maintained during cell division by the action of DNA methyltransferase 1 (DNMT1) (2.Portela A Esteller M. Epigenetic modifications and human disease.Nature Biotechnol. 2010; 28: 1057-1068Crossref PubMed Scopus (2001) Google Scholar). Recruited with other components of the DNA replication machinery during the S-phase, DNMT1 binds to hemimethylated CpG sites and methylates the CpG on the newly synthesized unmethylated daughter strand, thus propagating methylation patterns and ensuring the stability of the epigenetic code. On the other hand, de novo methylation is orchestrated predominantly by the action of DNMT3a and DNMT3b (2.Portela A Esteller M. Epigenetic modifications and human disease.Nature Biotechnol. 2010; 28: 1057-1068Crossref PubMed Scopus (2001) Google Scholar). These methyltransferases are capable of methylating unmodified CpG sites. De novo methylation primarily occurs during embryogenesis at the majority of CpG sites in the genome to establish the basal pattern of DNA methylation and subsequently targeted during early development to repress genes involved in pluripotency (12.Cedar H Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms.Nat Rev Genet. 2009; 10: 295-304Crossref PubMed Scopus (1698) Google Scholar). Following differentiation, cells lose their de novo methylation activity, and their DNA methylome is further maintained during cell replication through DNMT1 activity. Still, DNMT3a and DNMT3b are ubiquitously expressed at low levels in adult tissues, and certain circumstances can trigger de novo methylation of genes (12.Cedar H Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms.Nat Rev Genet. 2009; 10: 295-304Crossref PubMed Scopus (1698) Google Scholar). The reverse process, DNA demethylation, was initially thought to occur passively. Recent evidence, however, identified active demethylation through the ten-eleven translocation methylcytosine dioxygenases (TET1, TET2, or TET3). These enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) (13.Tahiliani M Koh KP Shen Y Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner T ET1.Science. 2009; 324 (et al): 930-935Crossref PubMed Scopus (4244) Google Scholar), leading to DNA demethylation (14.Ito S Shen L Dai Q Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.Science. 2011; 333 (et al): 1300-1303Crossref PubMed Scopus (2467) Google Scholar) (Figure 1). Global erasure of the methylome occurs at specific stages of mammalian development (15.Wu H Zhang Y. Reversing DNA methylation: Mechanisms, genomics, and biological functions.Cell. 2014; 156: 45-68Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar). However, TET proteins are also ubiquitously expressed at varying degrees in nondividing somatic cells, and active DNA demethylation can occur in most cell types (3.Schubeler D. Function and information content of DNA methylation.Nature. 2015; 517: 321-326Crossref PubMed Scopus (1265) Google Scholar). Some studies suggest that 5hmC is more than an intermediate to demethylation, having the potential to act as a bona fide epigenetic mark in its own right (16.Xu Y Wu F Tan L Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells.Mol Cell. 2011; 42 (et al): 451-464Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar). In highly expressed genes, 5hmC levels are low around the transcription start site and increase toward the 3′ end of the gene (16.Xu Y Wu F Tan L Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells.Mol Cell. 2011; 42 (et al): 451-464Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar). Moreover, hydroxymethylation is a stable DNA modification and tissues with differentiated, nonproliferating cell types have a higher 5hmC content (17.Bachman M Uribe-Lewis S Yang X 5-Hydroxymethylcytosine is a predominantly stable DNA modification.Nat Chem. 2014; 6 (et al): 1049-1055Crossref PubMed Scopus (354) Google Scholar). This is particularly true for the brain, but in the kidney, 5hmC levels are also relatively abundant (17.Bachman M Uribe-Lewis S Yang X 5-Hydroxymethylcytosine is a predominantly stable DNA modification.Nat Chem. 2014; 6 (et al): 1049-1055Crossref PubMed Scopus (354) Google Scholar). A comprehensive picture of the regulation of DNA methylation turnover is currently lacking (3.Schubeler D. Function and information content of DNA methylation.Nature. 2015; 517: 321-326Crossref PubMed Scopus (1265) Google Scholar). Still, it is evident that it is the interaction between different epigenetic players that ultimately determines gene expression. For example, the effect of DNMTs on DNA methylation is influenced by their interaction with histones and nucleosomes, while on the other hand, DNA methylation can also mediate histone and nucleosome modifications (2.Portela A Esteller M. Epigenetic modifications and human disease.Nature Biotechnol. 2010; 28: 1057-1068Crossref PubMed Scopus (2001) Google Scholar). In addition, genetic variability is an important determinant of the DNA methylation profile, probably mediated through variability in transcription factor binding, another factor influencing DNA methylation (3.Schubeler D. Function and information content of DNA methylation.Nature. 2015; 517: 321-326Crossref PubMed Scopus (1265) Google Scholar). Finally, environmental stimuli also can influence DNA methylation (1.Petronis A. Epigenetics as a unifying principle in the aetiology of complex traits and diseases.Nature. 2010; 465: 721-727Crossref PubMed Scopus (514) Google Scholar). In this review, we will additionally focus on factors that are relevant for transplantation research. We will now discuss how the major prognostic factors determining survival of kidney transplants are known to have a profound impact on DNA methylation. As such, there might be unanticipated roles for DNA methylation in determining the long-term outcome (Figure 2). Advanced donor age is one of the key variables determining worse long-term outcome of kidney transplantation (18.Metzger RA Delmonico FL Feng S Expanded criteria donors for kidney transplantation.Am J Transpl. 2003; 3 (et al): 114-125Crossref PubMed Scopus (517) Google Scholar). Several underlying mechanisms have been proposed, including telomere shortening, accumulation of somatic mutations, and oxidative stress, although their exact causality remains unclear (19.Naesens M. Replicative senescence in kidney aging, renal disease, and renal transplantation.Discov Med. 2011; 11: 65-75PubMed Google Scholar). Only recently, epigenetic changes accumulating during cellular senescence have been detected. Indeed, with advanced age the variability in DNA methylation patterns increases significantly, a process referred to as epigenetic drift (20.Hannum G Guinney J Zhao L Genome-wide methylation profiles reveal quantitative views of human aging rates.Mol Cell. 2013; 49 (et al): 359-367Abstract Full Text Full Text PDF PubMed Scopus (1764) Google Scholar). This increase in interindividual variability with advancing age is accompanied by an increase in methylation at sites with low methylation levels, such as CpG islands in promoters, and a decrease at sites with high methylation levels, such as nonisland CpGs (21.Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging Cell 2015.Google Scholar). Interestingly, the link between age and DNA methylation is robust and does not seem to depend on the microenvironment, as 1 year after allogeneic hematopoietic stem cell transplantation, DNA methylation in peripheral blood cells, which originate from the donor stem cells, still correlates with donor age but not with recipient age (22.Weidner CI Ziegler P Hahn M Epigenetic aging upon allogeneic transplantation: The hematopoietic niche does not affect age-associated DNA methylation.Leukemia. 2015; 29 (et al): 985-988Crossref PubMed Scopus (21) Google Scholar). It has furthermore been suggested that aging affects the epigenome in a tissue-specific manner. For instance, the promoter of N-cadherin, a cell adhesion molecule essential for cell polarity and thus renal function, is strongly methylated in aged, but not young, murine kidneys, which explains the age-dependent decrease in renal N-cadherin expression. Neither young or old rat livers display such a change in methylation or gene expression profile (23.Akintola AD Crislip ZL Catania JM Promoter methylation is associated with the age-dependent loss of N-cadherin in the rat kidney.Am J Physiol Renal Physiol. 2008; 294 (et al): F170-F176Crossref PubMed Scopus (32) Google Scholar). Besides the increased variability in DNA methylation with age, the methylation state at certain CpGs is highly correlated with age, to the extent that they can be used to accurately predict chronological age (21.Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging Cell 2015.Google Scholar). This process is referred to as the epigenetic clock. In this respect, a multitissue predictor of age was recently built by comprehensive analysis of publicly available DNA methylation data of 8000 samples encompassing 51 healthy tissues and cell types, including the kidney. At 353 CpGs across tissues, the methylation state predicted age (24.Horvath S. DNA methylation age of human tissues and cell types.Genome Biol. 2013; 14: R115Crossref PubMed Scopus (3028) Google Scholar). This illustrates that DNA methylation changes capture biological age, similar to telomere shortening. In addition, the deviations of the age estimated by DNA methylation analysis from the chronological age independently associated with increased mortality, suggesting that methylation-based age can provide an better estimate of future life span than chronological age (25.Marioni R Shah S McRae A DNA methylation age of blood predicts all-cause mortality in later life.Genome Biol. 2015; 16 (et al): 25Crossref PubMed Scopus (666) Google Scholar). Unfortunately, very little is known about age-related changes in the DNA methylome of the kidney. Moreover, the function of these epigenetic changes with age and the underlying mechanisms driving them are currently unknown (21.Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging Cell 2015.Google Scholar). The role of epigenetic dysregulation in allografts from older donors thus warrants additional investigation. Alloimmune responses to the allograft impede successful kidney transplantation and are characterized by the differentiation of progenitor and intermediate cell types to fully differentiated immune cells via a tightly regulated cascade of gene expression changes. Recent evidence supports a role for DNA methylation changes in orchestrating this process (Figure 3). Indeed, early on in hematopoiesis, hematopoietic stem cells differentiating into the myeloerythroid versus lymphoid lineage achieve markedly different methylation patterns (26.Bröske A-M. Vockentanz L Kharazi S DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction.Nat Genet. 2009; 41 (et al): 1207-1215Crossref PubMed Scopus (368) Google Scholar, 27.Ji H Ehrlich LI Seita J Comprehensive methylome map of lineage commitment from haematopoietic progenitors.Nature. 2010; 467 (et al): 338-342Crossref PubMed Scopus (490) Google Scholar). In addition, active demethylation by TET2-mediated hydroxymethylation is involved in the differentiation of peripheral blood monocytes into macrophages and dendritic cells (28.Klug M Heinz S Gebhard C Active DNA demethylation in human postmitotic cells correlates with activating histone modifications, but not transcription levels.Genome Biol. 2010; 11 (et al): R63Crossref PubMed Scopus (68) Google Scholar, 29.Klug M Schmidhofer S Gebhard C 5-Hydroxymethylcytosine is an essential intermediate of active DNA demethylation processes in primary human monocytes.Genome Biol. 2013; 14 (et al): R46Crossref PubMed Scopus (73) Google Scholar, 30.Zhang X Ulm A Somineni HK DNA methylation dynamics during ex vivo differentiation and maturation of human dendritic cells.Epigenet Chromatin. 2014; 7 (et al): 21Crossref PubMed Scopus (67) Google Scholar). Also, in the activation of macrophages toward the two distinct polarized M1 (representing the “classic” activation of macrophages, associated with proinflammatory responses) and M2 (representing the “alternative” activation, associated with anti-inflammatory responses and tissue remodeling) phenotypes, differential DNA methylation is involved. Inhibition of DNMT3B is namely able to skew macrophages toward the M2 phenotype (31.Yang X Wang X Liu D Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b.Mol Endocrinol. 2014; 28 (et al): 565-574Crossref PubMed Scopus (135) Google Scholar). Interestingly, M2 macrophages are involved in renal regeneration by generating mediators that support tubular survival and proliferation to restore tubular integrity (32.Lee S Huen S Nishio H Distinct macrophage phenotypes contribute to kidney injury and repair.J Am Soc Nephrol. 2011; 22 (et al): 317-326Crossref PubMed Scopus (622) Google Scholar, 33.Schmidt IM Hall IE Kale S Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function.J Am Soc Nephrol. 2013; 24 (et al): 309-319Crossref PubMed Scopus (84) Google Scholar, 34.Lin SL Li B Rao S Macrophage Wnt7b is critical for kidney repair and regeneration.Proc Natl Acad Sci U S A. 2010; 107 (et al): 4194-4199Crossref PubMed Scopus (332) Google Scholar). This epigenetic regulation of macrophage polarization thus supports the idea of a continuum of macrophage phenotypes, rather than fixed polarized phenotypes (35.Alvarez-Errico D Vento-Tormo R Sieweke M Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function.Nat Rev Immunol. 2015; 15: 7-17Crossref PubMed Scopus (223) Google Scholar). Epigenetics are also involved in the differentiation of naïve CD4+ T cells toward effector T-helper cells (Th1, Th2, and Th17) or regulatory T (Treg) cells (36.Wilson CB Rowell E Sekimata M. Epigenetic control of T-helper-cell differentiation.Nat Rev Immunol. 2009; 9: 91-105Crossref PubMed Scopus (550) Google Scholar). For example, the segregation of the Th1 and Th2 cells based on their mutually exclusive production of interferon-γ or interleukin-4 (IL-4), IL-5, and IL-13, respectively, is characterized by their corresponding different DNA methylation profiles (37.Schoenborn JR Dorschner MO Sekimata M Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma.Nat Immunol. 2007; 8 (et al): 732-742Crossref PubMed Scopus (243) Google Scholar). Also for Treg cells that constitutively express Foxp3, a transcription factor necessary for its suppressive function, maintaining a stable expression of Foxp3 relies on DNA demethylation of a CpG-rich region within the Foxp3 locus early in thymic Treg development (38.Lal G Zhang N van der Touw W Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation.J Immunol. 2009; 182 (et al): 259-273Crossref PubMed Scopus (457) Google Scholar, 39.Baron U Floess S Wieczorek G DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells.Eur J Immunol. 2007; 37 (et al): 2378-2389Crossref PubMed Scopus (547) Google Scholar, 40.Toker A Engelbert D Garg G Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus.J Immunol. 2013; 190: 3180-3188Crossref PubMed Scopus (191) Google Scholar). In B cells that are activated in the germinal center by antigenic stimulation, global reprogramming of the DNA methylome occurs (41.Lai AY Mav D Shah R DNA methylation profiling in human B cells reveals immune regulatory elements and epigenetic plasticity at Alu elements during B-cell activation.Genome Res. 2013; 23 (et al): 2030-2041Crossref PubMed Scopus (80) Google Scholar). Thereafter, when differentiating into memory B cells or plasma cells, the DNA methylome remains mostly unaltered, providing a platform for memory B cells to rapidly differentiate into plasma cells on antigen rechallenge (41.Lai AY Mav D Shah R DNA methylation profiling in human B cells reveals immune regulatory elements and epigenetic plasticity at Alu elements during B-cell activation.Genome Res. 2013; 23 (et al): 2030-2041Crossref PubMed Scopus (80) Google Scholar). Because epigenetic mechanisms determine thus both lineage stability and lineage plasticity, targeting the epigenome could be promising as a therapeutic strategy to prolong kidney transplantation, especially in the era of cell therapy in transplantation medicine. For example, Treg cell therapy might improve allograft survival but is hampered by the loss of FOXP3 expression during cell expansion and transfusion. The inhibition of DNA methylation by DNMT inhibitors could potentially promote more stable FOXP3 expression in Tregs (42.Lal G Bromberg JS. Epigenetic mechanisms of regulation of Foxp3 expression.Blood. 2009; 114: 3727-3735Crossref PubMed Scopus (285) Google Scholar). In addition, epigenetic therapies could be applied to skew macrophages toward the regenerative, anti-inflammatory M2 phenotype and induce less deleterious rejection phenotypes (31.Yang X Wang X Liu D Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b.Mol Endocrinol. 2014; 28 (et al): 565-574Crossref PubMed Scopus (135) Google Scholar). The compelling aspects of therapy targeting the epigenome are discussed in the preceding section. Further, there is an unmet need for monitoring the immune response in transplant recipients because sufficiently robust biomarkers to predict long-term outcome are currently lacking. In oncology, aberrant DNA methylation patterns are used for cancer detection, prognosis, and prediction of therapeutic responses (43.Laird PW. The power and the promise of DNA methylation markers.Nat Rev Cancer. 2003; 3: 253-266Crossref PubMed Scopus (1274) Google Scholar). Only a few studies evaluated the role of DNA methylation in transplantation medicine. In kidney transplant recipients with subclinical rejection, long-term allograft outcome was better when FOXP3+ Treg cells were present in allograft biopsy samples. In these FOXP3+ Treg cells, a locus near FOXP3 was unmethylated, which distinguishes them from effector T cells, thus serving as a protective biomarker (44.Bestard O Cunetti L Cruzado JM Intragraft regulatory T cells in protocol biopsies retain foxp3 demethylation and are protective biomarkers for kidney graft outcome.Am J Transplant. 2011; 11 (et al): 2162-2172Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Likewise, in hematopoietic stem cell transplantation, DNA methylation at genes encoding interferon-γ, Fas ligand, and IL-10 was associated with the severity of graft-versus-host disease (45.Rodriguez RM Suarez-Alvarez B Salvanes R DNA methylation dynamics in blood after hematopoietic cell transplant.PloS ONE. 2013; 8 (et al): e56931Crossref Scopus (15) Google Scholar). DNA methylation markers can thus be used to assess the renal cell composition and monitor the immune response in transplanted patients. Moreover, DNA methylation entails advantages over proteins and RNA as a biomarker of immune activation by being more accessible, which is discussed in the last section of this minireview. Finally, besides controlling immune cell differentiation and activation, epigenetic regulators are themselves susceptible to inflammation and immune responses. For instance, IL-6 is able to elicit epigenetic changes by regulating DNMT expression (46.Hodge DR Peng B Cherry JC Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation.Cancer Res. 2005; 65 (et al): 4673-4682Crossref PubMed Scopus (186) Google Scholar). Moreover, several associations between chronic inflammation and epigenetic alterations have been observed (47.Issa J-P. Aging and epigenetic drift: a vicious cycle.J Clin Invest. 2014; 124: 24-29Crossref PubMed Scopus (254) Google Scholar). Although these studies suggest an impact of inflammation on epigenetics, much more work needs to be done to understand the relevance of this link. Another factor that adversely impacts kidney transplantation outcome is ischemia–reperfusion injury occurring during transplantation. Indeed, prolonged cold ischemia is associated with increased risk of delayed graft function (48.Ojo AO Wolfe RA Held PJ Delayed graft function: risk factors and implications for renal allograft survival, 1.Transplantation. 1997; 63 (et al): 968-974Crossref PubMed Scopus (839) Google Scholar), diminished allograft function (49.Salahudeen AK Haider N May W. Cold ischemia and the reduced long-term survival of cadaveric renal allografts.Kidney Int. 2004; 65: 713-718Abstrac" @default.
• W2256910130 created "2016-06-24" @default.
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• W2256910130 date "2016-04-01" @default.
• W2256910130 modified "2023-10-05" @default.
• W2256910130 title "The Emerging Role of DNA Methylation in Kidney Transplantation: A Perspective" @default.
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