Yiouli P. Ktena
Margarita Dionysiou- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
The field of epigenetics studies the complex processes that regulate gene expression without altering the DNA sequence itself. It is well established that epigenetic modifications are crucial to cellular homeostasis and differentiation and play a vital role in hematopoiesis and immunity. Epigenetic marks can be mitotically and/or meiotically heritable upon cell division, forming the basis of cellular memory, and have the potential to be reversed between cellular fate transitions. Hence, over the past decade, there has been increasing interest in the role that epigenetic modifications may have on the outcomes of allogeneic hematopoietic transplantation and growing enthusiasm in the therapeutic potential these pathways may hold. In this brief review, we provide a basic overview of the types of epigenetic modifications and their biological functions, summarizing the current literature with a focus on hematopoiesis and immunity specifically in the context of allogeneic hematopoietic stem cell transplantation.
Introduction
Every cell in the human body carries the same genetic code, yet only a subset of genes is actively expressed at any given time-point in any given cell, in an intricate process that is orchestrated by epigenetics. In the Greek language, “epi” signifies on, upon, or over. Accordingly, the field of epigenetics studies the processes that affect gene expression without altering the DNA sequence itself, the sum of which is described as the epigenome (1, 2).
Epigenetic modifications include DNA methylation, histone modification, Chromatin remodeling, and non-coding RNA regulation (1–3). In brief, a nucleosome, chromatin’s basic structural unit, is comprised of negatively charged DNA packed around a positively charged histone octamer. Chemical alterations to this complex can allow or prevent access of the transcriptional machinery to the DNA sequence. Broadly, epigenetic regulators may be classified as “writers”, “readers”, and “erasers”. Writers include a wide variety of enzymes that introduce modifications on DNA and histones, including DNA methyltransferases, histone methyltransferases, histone acetyltransferases. Readers encompass proteins with domains that recognize and bind specific epigenetic modifications, such as methyl-CpG-binding proteins, histone methylation binding proteins, and histone acetylation binding proteins. Finally, erasers represent proteins which actively remove epigenetic marks and reverse the effects on transcription, such as TET (ten-eleven translocation) proteins which catalyze cytosine demethylation, histone demethylases, and histone deacetylases (4).
Many of these changes can be mitotically and/or meiotically heritable on nascent daughter chromatin strands upon cell division. This results in a type of cellular memory termed epigenetic memory. At the same time, epigenetic modifications are characterized by plasticity in response to factors intrinsic and extrinsic to the cell, such as environmental stimuli (5–7). Therefore, not only can these modifications somatically be inherited after cell division and repress target gene transcription, but they can also be reversed during transitions between cellular fates, making them the focus of significant scientific investigation.
Mechanisms of epigenetic modification
DNA methylation is the most widely studied form of epigenetic modification and generally results in gene silencing. It primarily involves methylation of cytosine residues almost exclusively in the context of CpG dinucleotides. CpG dinucleotides cluster in regions termed CpG islands, where approximately 60% of human gene promoters are located. However, tissue-specific DNA methylation and differential methylation associated with reprogramming are mostly located in regions adjacent to each side of a CpG island, termed shores (1–3). Of the five known human DNA methyltransferases, DNMT1 is thought to be primarily responsible for maintenance methylation, while DNMT3A and DNMT3B are the primary de novo methyltransferases. DNMT3L lacks enzymatic activity but interacts with other enzymes and plays a role in maternal imprinting (8, 9).
Histone modifications, at various sites, include methylation (which most commonly represses transcription), acetylation (usually activating in nature), phosphorylation (which contributes to chromatin remodeling and assists in DNA repair), ubiquitylation, and others (1–3, 7). These modifications, along with histone variants within nucleosomes (histones characterized by minor differences in their amino acid sequence from their canonical counterpart) can also result in nucleosome repositioning and chromatic remodeling, such that transcription sites are more or less accessible to interact with transcriptional machinery (1, 3). These chromatin markers and the associated epigenetic signatures have shown to be reversible (1).
Lastly, non-coding RNAs (ncRNAs), particularly regulatory ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small interfering RNAs (siRNAs) and piwi-interacting RNAs (piRNAs), are transcribed (but non-translated) RNA molecules believed to fine-tune gene expression by contributing to gene silencing. Moreover, non-coding RNAs are known to interact with and guide chromatin-modifying complexes to the appropriate genomic targets (1–3, 5, 7). Notably, the aforementioned epigenetic mechanisms are functionally linked and interdependent, with continuous cross-talk involving both positive and negative feedback.
Epigenetics in human development, health, and disease
Epigenetic processes appear to have an instrumental role in human development, health, and disease (7, 10). In the earliest stages of embryogenesis, the epigenome is “reset”. As the zygote, in its one cell glory, transitions from totipotency to pluripotency in the blastocyst stage, complex epigenetically controlled mechanisms guide each cell towards a differentiated state and limit plasticity to maintain a fixed cell type (11, 12). Highlighting the importance of epigenetics in embryogenesis is the fact that Dnmt3a- and/or Dnmt3b-null mice die during gestation or shortly after birth (13).
As suggested, epigenetic dysregulation can disrupt cellular homeostasis and has been implicated in various diseases (6, 7, 14, 15). Disorders affecting genomic imprinting can result in distinct clinical syndromes, such as Beckwith-Wiedemann, Russell-Silver, and Prader-Willi/Angelman syndromes (16), while germline DNMT3A mutations can result in Tatton-Brown-Rahman syndrome (17, 18). In the early eighties, global DNA hypomethylation was first described in cancer. Subsequent work revealed that focal DNA hypermethylation of tumor suppressor genes facilitates stem-like cell behavior in the pathophysiology of carcinogenesis (19–22). Mutations in DNMT3A (the product of which catalyzes de novo DNA methylation), TET2 (responsible for regulated demethylation), and ASXL1 (involved in chromatin regulation), are the most frequently described mutations in clonal hematopoiesis, including clonal hematopoiesis of indeterminate potential (CHIP) and myeloid malignancies such as myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) (23–25). CHIP has been recently identified as a new precursor state for myeloid malignancies (26, 27). Specific types of histone modifications and microRNAs have also been linked to a multitude of malignancies (28–31). In this context, an ever-increasing number of epigenetically targeted therapies have been developed and applied in the care of cancer patients, whether alone or in combination with traditional chemotherapy, targeted agents, or immunotherapy (32, 33). Epigenetic mechanisms with therapeutic potential have also been implicated in neurodegenerative disorders (3, 34).
Epigenetic regulation of hematopoietic stem cells, before and after transplantation
Hematopoietic stem cells (HSCs) are characterized by self-renewal and pluripotency, features that are of paramount importance to the biological functions of hematopoiesis and immunity. As multipotent progenitors arise from HSCs and further commit to the myeloid or lymphoid lineage, epigenetic regulators define the major differentiation and maintenance events (14). In particular, DNA methylation plays a crucial role in these processes. Epigenetic factors are also associated with cellular senescence, the inevitable cessation in proliferation that characterizes biological aging. In HSCs, cellular aging is associated with a relative increase in the myeloid component, enhanced autoimmunity, accrual of DNA damage, and an increased risk of hematologic neoplasms (35). Genome-wide studies of HSCs show distinct differences in the epigenomic landscape of aging cells with several regions of differential DNA methylation having potential relevance for age-related disease (36). Dnmt1 deletion in murine HSCs results in rapid death from profound pancytopenia due to absence of all HSCs and progenitors, while low-level Dnmt1 expression results in a marked decrease of lymphoid progenitors and decreased self-renewal capacity in serial transplantation experiments (37). Dnmt3a/Dnmt3b-deficiency in murine HSCs leads to a decline in their differentiation potential with accumulation of hematopoietic progenitors in the marrow. Furthermore, Dnmt3a-null and Tet2-null cells have a competitive expansion and survival advantage in serial transplantation experiments (38–43). ASXL1 proteins are epigenetic regulators that recruit chromatin modification complexes and transcription factors; in mice, Asxl1 deficiency in HSCs results in myelodysplasia with accumulation of hematopoietic progenitors but decreased self-renewal, and serial transplantation of Asxl1-null HSCs results in acceleration of a lethal myelodysplastic disorder as compared to primary Asxl1 KO mice (44). Tet2-deficient mice demonstrate increase hematopoietic self-renewal and compound Asxl1 and Tet2 loss restores the Asxl1-loss related self-renewal defect and results in more severe MDS-like features. These findings are in accordance with the fact that DNMT3A, TET2, and ASXL1 mutations are some of the most common genetic abnormalities in clonal hematopoiesis and are frequently detected, alone or in combination, in patients with hematological malignancies (23, 45–48).
In the post-transplant setting, allogeneic hematopoietic stem cell transplantation (HSCT) recipients have been found to stably maintain the donor’s global methylation status, and differences in global methylation correlate with the evolution of mixed chimerism (49). Moreover, donor methylation levels in the promoters of critical genes such as IFNG and FASL correlate with the severity of acute graft-versus-host disease (GVHD), suggesting they could be used alongside HLA typing to optimize donor selection (49). Apart from specific DNA methylation signatures, the “epigenetic age” of donor HSCs appears to be cell-intrinsic, and thus remains largely stable after transplantation in concordance with the chronological age of the donor. As such, epigenetic age is not influenced by the recipient’s chronological age, even decades after transplantation (50–52). In two separate studies, patients whose donor stem cells exhibited accelerated aging, as determined by the “epigenetic clock”, were at higher risk of developing chronic GVHD (53, 54). In xenogeneic murine models of HSCT, this phenomenon is again thought to be cell-intrinsic, rather than host-dependent (55).
Importantly, several studies have now linked donor CHIP to HSCT outcomes. A European study identified 92 clonal mutations in 500 healthy donors over the age of 55; donor CHIP, especially DNMT3A-driven CHIP, was associated with increased incidence of chronic GVHD and decreased incidence of relapse or progression. Subsequently, a large US-based study of over 1,700 donors over the age of 40 further confirmed these findings. Additional data suggest that donor DNMT3A mutations are independently associated with improved overall survival due to reduced risk of relapse (56–58). Of note, this phenomenon appears to be eliminated by the administration of post-transplantation cyclophosphamide for the prevention of GVHD, suggesting that it is at least partially mediated by DNMT3A-mutated donor T-cells, the function of which is altered by cyclophosphamide (58, 59). In these studies, there was a very low risk of donor CHIP evolution to donor cell leukemia (DCL): 2 recipients of 82 mutated grafts in the first study and 6 recipients of 388 mutated grafts in the second (56, 58, 60). No recipients with sole mutations in DNMT3A or TET2 developed DCL. Two smaller studies also examined the CHIP-alloreactivity link: A single-center study found increased risk of acute GVHD but not chronic GVHD and no differences in incidence of relapse; notably, this study included a large number of high-risk patients, with over half of the cohort having active disease at the time of transplantation (61). A more recent study also failed to replicate the results from the larger studies, likely due to the significantly limited sample size (only 25 mutated donor products were identified, with an unusual distribution of CHIP mutations, potentially due to thefact that donors as young as 17 were included) (62). GVHD following liver transplantation (LT-GVHD) is a rare complication, associated with bone marrow failure and a hyperinflammatory state; in a case series of 9 patients where 7 bone marrow samples were available for next generation sequencing, DNMT3A mutations were found in 5 out of 7 samples, as compared to 1 of 6 in a LT-non-GVHD cohort (63).
In accord with these clinical observations, laboratory data showed an increase in both acute and chronic GVHD when T-cell lineage-specific Dnmt3a-null mice were used as donors in multiple murine allogeneic HSCT models (58, 64). These observations were associated with early proliferation of donor-derived Dnmt3a-null T-cells as compared to wild-type T-cells. Furthermore, Dnmt3a-null T-cells demonstrated a migration advantage to the gastrointestinal tract and secondary lymphoid organs, enhanced pro-inflammatory cytokine production, and decreased expression of exhaustion and apoptosis markers (64). A comprehensive review of the epigenome and transcriptome of Dnmt3a-null donor T-cell subsets post-HSCT, via whole genome bisulfite sequencing and in parallel, bulk RNA sequencing, showed similar global DNA methylation levels to wild-type T-cells but distinct hypomethylation peaks in gene pathways involved with T-cell activation and differentiation. More importantly, donor T-cells lacking DNMT3A provided superior tumor control in graft-versus-leukemia models, corroborating the clinical data cited above (64). In gene-set enrichment analyses of the genes differentially expressed between Dnmt3a-null and WT donor T-cells, CD8+ T-cells lacking DNMT3A were highly enriched for effector-like signatures and negatively enriched for exhaustion-like signatures, while CD4+ T-cells were enriched for genes expressed in activated and progenitor cell populations.
These observations are consistent with a growing body of data showing that DNA methylation critically contributes to the functional properties that define T-cell identity. For example, DNMT3A is selectively upregulated 38-fold following T-cell receptor stimulation and subsequently regulates T-helper cell polarization and effector T-cell differentiation, depending on the context of cellular activation (65–67). Following differentiation and activation, the patterns of gene expression that define T-cell subsets are stabilized through DNA methylation. T-cell deletion of DNMT3A enhances the plasticity of T-helper cells by allowing for reprogramming of cytokine expression, and allows CD8+ T-cells to overcome epigenetically-defined exhaustion programs in order to more effectively clear chronic infections (65–71). DNMT3A deletion also appears to enhance the anti-tumor effects of T-cells whether in the context of immune-checkpoint inhibition, chimeric-antigen receptor (CAR) T-cells, or allogeneic HSCT (64, 71, 72). Akin to what was observed in murine models of allo-HSCT, deletion of DNMT3A in CAR T-cells resulted in exhaustion-resistant cells with preservation of the cells’ proliferative capacity and ongoing anti-tumor response despite prolonged tumor exposure (72, 73).
Since epigenetic dysregulation is common in neoplasia, and given the reversible nature of epigenetic alterations, pharmacologic agents targeting epigenetic regulators are now regularly used in the treatment of cancer patients (32). Azacitidine and decitabine, the two most widely used hypomethylating agents, are nucleoside analogs that bind and inhibit DNA methyltransferases after being incorporated into newly formed DNA. Both drugs have received FDA approval for the treatment of MDS, AML, and chronic myelomonocytic leukemia. However, both agents are non-specific and despite not being categorized as traditional chemotherapy do have cytotoxic potential, giving rise to adverse events secondary to myelosuppression (32). In addition to their anti-tumor effects, the immune-modulatory potential of azacitidine and decitabine is appealing both in the pre- and post-transplantation setting. Prior to HSCT, these agents are used alone or in combination to decrease disease burden and serve as a bridge to transplant, especially in older patients with MDS and AML (74–77). In the post-transplantation period, there is growing interest in strategies that will help prevent relapse, which is a major driver of mortality (77–79). Preclinical and clinical data suggested that azacitidine may mitigate GVHD without compromising graft-versus-leukemia (GVL) activity (80–82). However, a phase III randomized clinical trial of azacitidine maintenance versus observation post-HSCT for high-risk AML/MDS patients failed to improve relapse-free survival (79, 83). Low-dose decitabine may be more promising, whether alone or in combination with other agents (84, 85). Next-generation DNMT inhibitors, such as guadecitabine, appear to have an improved toxicity profile, and non-nucleoside inhibitors, which have the potential to be more potent and selective, are in development (32, 86).
Histone modifications have been widely targeted in the context of neoplasia and allogeneic HSCT, with several agents inhibiting histone deacetylases now commercially available including but not limited to vorinostat, panobinostat, belinostat, and romidepsin (28, 87, 88). Histone modifications contribute to the regulation of proliferation and cytotoxicity in activated T-cells and histone acetylation was one of the first epigenetic modifications to be studied in preclinical models of acute GVHD (87). Histone deacetylase (HDAC) inhibitors were found to decrease the allo-stimulatory function of dendritic cells, a group of potent antigen-presenting cells known to be instrumental in the induction of acute GVHD, as well as enhance natural regulatory T-cell function, and hence reduce GVHD while preserving GVL effects (89–92). As a result, one of these agents, suberoylanilide hydroxamic acid (SAHA, now known as vorinostat) was tested in two phase I/II trials (NCT00810602, NCT01790568; a third, NCT03842696, underway) for the prevention of GVHD in combination with standard therapy and was found to be safe and potentially effective (93, 94). Panobinostat also showed promising results in two phase I/II studies (NCT01111526, NCT02588339) (95, 96). Results from a phase III trial of panobinostat as post-HSCT maintenance therapy are pending (NCT04326764) (79). Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that catalyzes histone 3 lysine 27 trimethylation, a modification that represses gene transcription and is thought to be involved in T-cell immune responses (87). Pharmacologic inhibition of histone methylation via DZNep, an inhibitor that depletes EZH2, was found in one study to arrest ongoing GVHD in mice by inducing apoptosis of alloreactive T-cells without inhibiting donor-derived hematopoiesis or GVL activity (97, 98). However, these findings were not replicated with other agents or in a xenogeneic model using DZNep (99).
Bromodomain and extraterminal (BET) proteins regulate chromatin dynamics by binding acetylated lysine residues in histones and nonhistone proteins, including transcription factors; given the therapeutic potential, BET inhibitors targeting the acetyl-binding domains of these proteins have been developed (100). In murine models of GVHD, BET inhibition suppressed GVHD by altering the cytokine expression profiles of dendritic cells and T-cells, with retention of anti-tumor effects, while certain inhibitors also allow for infused Treg expansion as a combinatorial strategy (101, 102). More recently, Snyder et al. reported on two potent and selective BET inhibitors which improve survival and reduce GVHD severity in mice without sacrificing the beneficial GVL effect; PLX51107 is currently being tested in a phase I/II trial for steroid-refractory acute GVHD (NCT04910152) (103). Both EZH2 inhibition and BET-bromodomain inhibition demonstrated activity in preclinical models of chronic GVHD with lung involvement, with evidence of altered transcriptomes in the germinal centers of treated animals (104).
The role of non-coding RNAs, mainly microRNAs, in T-cell immunobiology is well established and is increasingly being explored in the context of hematopoiesis and allogeneic HSCT (105, 106). Several microRNAs are emerging as important regulators of allogeneic T-cells and may prove to be highly sensitive and specific biomarkers for GVHD and useful targets for anti-GVHD oligonucleotide-based therapeutics (105–108). Ranganathan et al., showed increased expression of microRNA-155 (miR-155) in both CD4- and CD8-positive cells following murine allo-HSCT, as well as ameliorated GVHD in multiple KO and antagonist-treated models and worse phenotype in over-expression models (109). MicroRNA-155 also influences GVHD via its function in recipient dendritic cells. In study by Chen et al., miR-155–deficient dendritic cells cause less severe GVHD through reduced migration and defective inflammasome activation, supported by the fact that Nlrp3/miR-155 double-knockout allo-HSCT recipient mice had no increased protection from GVHD compared with Nlrp3−/− recipients (110). The role of the microRNA-17-92 cluster in allo-HSCT was explored in a similar study that utilized a T cell-specific KO model, and showed reduced GVHD by demonstrating defects in proliferation, cytokine production and α4β7 integrin expression in KO T cells (111). MicroRNA-146a has a protective role in GVHD, and its anti-GVHD effects were demonstrated in several studies, via its function in both allogeneic T-cells and recipient dendritic cells (112–114). MicroRNA-31 promotes murine chronic GVHD via T-cell metabolic pathway regulation (108). Differential microRNA expression has been detected in skin biopsies of patients at the time of onset of cutaneous acute GVHD, and circulating microRNAs encapsulated within extracellular vesicles were found differentially expressed in patients with chronic GVHD (115, 116). Several long non-coding RNAs (lncRNAs) have been found to influence the function of T-cells, but their role in allo-immune responses is still unknown. Linc00402 was recently identified as a long non-coding RNA that regulates T-cell function in humans and experimental murine models. RNA sequencing was performed on human T-cells after HSCT and solid organ (cardiac) transplant and compared to T-cells from healthy subjects. Linc00402, a T-cell specific molecule, was found to be differentially expressed in recipients of allogeneic mismatched unrelated as compared to autologous HSCT patients, and in donor T-cells from patients who underwent cardiac transplantation. In contrast, in vitro and murine in vivo data showed that T-cell activation and proliferation are inversely related to Linc00402 expression, and that depletion of Linc00402 impairs the allogeneic stimulation of T-cells ex vivo. The authors hypothesized that higher levels of tacrolimus exposure were the culprit for the preservation of Linc00402 abundance in allogeneic HLA-mismatched HSCT. Importantly, the tissue-specific and allogeneic context-specific expression of this molecule, along with its immune regulatory properties, make for an appealing therapeutic candidate (117, 118). In a study by Wang et.al, numerous lncRNAs were found to be dysregulated in B cells from patients with chronic graft-versus-host disease (cGVHD) as compared to normal counterparts. Specifically, lncRNAs NONHSAT040475, NONHSAT142151 and FR118417 were found to be strongly associated with the BCR signaling pathway in cGVHD pathogenesis (119). Another class of non-coding RNAs, termed circular RNAs, has been associated with increased relapse risk in AML patients (120).
In sum, the maintenance and differentiation of hematopoietic stem cells require epigenetic regulatory networks that are 1) simultaneously heritable and reversible, 2) responsive to both intrinsic and extrinsic stimuli, and 3) characterized by interdependence between the DNA sequence, transcriptional processes, and the various forms of epigenetic changes. Despite the evident importance of epigenetic modifications in hematopoiesis and alloreactivity, the exact mechanistic underpinnings of how epigenetics operate in each context continue to elude the scientific community. Future challenges exist not merely in uncovering the full spectrum of epigenetic circuits, but equally importantly, in defining exactly how these complex, interactive, and frequently conflicting pathways ultimately affect donor stem cells, immune cell reactivity, and HSCT outcomes. As the field of epigenetics continues to steadily evolve, HSCT patients will undoubtedly benefit from the knowledge that is yet to be fully appreciated.
Author contributions
Conception: YK and KC. Literature review: YK, MD, LG, and KC. Manuscript writing: YK, MD, LG, and KC. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: bone marrow transplant (BMT), allogenetic hematopoietic stem cell transplantation, DNA methylation, epigenetics, GvHD, histone modifications, non-coding RNA
Citation: Ktena YP, Dionysiou M, Gondek LP and Cooke KR (2023) The impact of epigenetic modifications on allogeneic hematopoietic stem cell transplantation. Front. Immunol. 14:1188853. doi: 10.3389/fimmu.2023.1188853
Received: 17 March 2023; Accepted: 18 May 2023;
Published: 31 May 2023.
Edited by:
Daniel Peltier, University of Michigan, United StatesReviewed by:
Huidong Guo, Peking University People’s Hospital, ChinaParvathi Ranganathan, The Ohio State University, United States
Copyright © 2023 Ktena, Dionysiou, Gondek and Cooke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yiouli P. Ktena, yktena1@jh.edu