How can epigenetics

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Reprints and Permissions. Atlante, S. The epigenetic implication in coronavirus infection and therapy. Clin Epigenet 12, Download citation. Received : 23 July But that is only part of the story—the environment in which one develops , before and soon after birth, provides powerful experiences that chemically modify certain genes which, in turn, define how much and when they are expressed.

Thus, while genetic factors exert potent influences, environmental factors have the ability to alter the genes that were inherited. Although frequently misunderstood, adverse fetal and early childhood experiences can—and do—lead to physical and chemical changes in the brain that can last a lifetime. Despite some marketing claims to the contrary, the ability of so-called enrichment programs to enhance otherwise healthy brain development is not known.

While parents and policymakers might hope that playing Mozart recordings to newborns will produce epigenetic changes that enhance cognitive development, there is absolutely no scientific evidence that such exposure will shape the epigenome or enhance brain function. We also know that sound maternal and fetal nutrition , combined with positive social-emotional support of children through their family and community environments, will reduce the likelihood of negative epigenetic modifications that increase the risk of later physical and mental health impairments.

Epigenetics explains how early experiences can have lifelong impacts. Young brains are particularly sensitive to epigenetic changes. The absence of miR mitigated stress responsivity and facilitated fear extinction. The levels of certain stress-related proteins have been analyzed. Similarly, Andolina et al.

MiR levels were assessed in all of the main areas that are involved in stress responses, peaking in DRN. Recent results Andolina et al. There is evidence of epigenetic changes in humans throughout life and several extensive reviews, many of which have focused on alterations in the stress response and psychopathologies Faa et al.

Anxious individuals have higher global methylation levels compared with nonanxious controls Murphy et al. Specifically, social anxiety disorder, for example, is associated with decreased OXTR methylation and greater cortisol release and amygdalar activation in response to anxiety-related triggers Ziegler et al. Another important gene, glutamate-decarboxylase 1 GAD1 , encoding a crucial glutamatergic metabolic factor, is undermethylated in patients with panic disorder Domschke et al.

Chronic psychosocial stress has been associated with hypermethylation of the NR3C1 gene Witzmann et al. In contrast, a previous study has shown a reduction in GR-stimulated gene expression with higher blood levels of cortisol in major depressive disorder Menke et al. Notably, antidepressant treatment alters BDNF expression in the prefrontal cortex in humans Chen et al.

Finally, higher methylation levels in the serotonin transporter gene SLC6A4 correlates with a positive response to psychotherapy Roberts et al. The function of various miRNA families in environmental adaptation has been established in clinical studies. The causal relationships with such epigenetic markers, however, are often undefined.

For example, the blood levels of miR correlate negatively with psychiatric symptoms of anxiety Chen S. Similarly, by microarray, the expression of several miRNAs in the blood of bipolar and depressed patients has been measured, wherein disorder-specific and commonly altered miRNAs have been identified Maffioletti et al.

In these cases, such alterations in epigenetic markers could be caused by genetic polymorphisms, epigenetic adaptation to certain environmental conditions, or both. In patients with major depressive disorder who respond poorly to antidepressant treatment, the blood levels of several miRNAs are altered, particularly those that are involved in nucleotide binding and chromatin assembly; consequently, four putative miRNAs that were predictive of treatment outcome were identified Belzeaux et al.

Given the technical constraints of clinical research, there is little direct evidence of altered patterns in the brain. Several postmortem studies have reported significant downregulation of key miRNAs in the prefrontal cortex of depressed suicide subjects Smalheiser et al. There are many factors that affect the offspring epigenetically during pregnancy, in a process that is termed fetal programming Faa et al.

The concept of fetal programming refers to all of the adaptations to the intrauterine and maternal environment that shape the developing individual structurally and functionally Swanson et al.

Maternal epigenetic factors that are active during gestation and interfere with neurodevelopment have been grouped into two overarching categories: maternal and fetal. Maternal factors include maternal diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance use and exposure to environmental toxicants Al-Gubory, ; Lyall et al.

Maternal hormones, immune factors, nutrients and odors can be even modified by the presence of the father, who thus appears to have an influence even during gestation Todrank et al. For example, maternal fat diet increases the susceptibility of male offspring to liver disease through epigenetic reprogramming of lipid metabolism and inflammatory responses Pruis et al. Further, prenatal undernutrition, for example, can permanently alter DNA methylation in the sperm of adult offspring in regions that are resistant to zygotic reprogramming, potentiating transgenerational transmission of metabolic disorders Radford et al.

Maternal immune activation, in contrast, predisposes the offspring to depression Ronovsky et al. Exposure to testosterone during pregnancy—for example, due to polycystic ovary syndrome—can affect the limbic system of offspring in rats and contribute to elevated anxiety-like behavior Hu et al.

Experience with prenatal gastrointestinal stress in rodent dams engenders anxiety-like and depression-like behaviors in adult offspring Zheng et al.

Placental miRNAs have been implicated by several groups Maccani et al. There are many studies on the effects of the maternal environment during pregnancy on offspring in humans, but none demonstrated that these outcomes are mediated by epigenetics directly.

As reviewed by Faa et al. Similarly, smoking during pregnancy favors premature birth and motor, memory and behavioral deficits. Stress is a significant mediator of vulnerability, and it has been hypothesized that excess cortisol, due to maternal anxiety, induces neurodevelopmental damage in the fetus after crossing the placental barrier Dorrington et al.

Maternal stress can disrupt GABAergic inhibitory transmission, leading to anxiety or maladaptation to stressors in the offspring Fine et al. Conradt et al. Impaired production of this protein results in a leaky placenta that does not adequately protect the offspring from the detrimental effects of excess cortisol. There is even less evidence on the function of miRNAs in epigenetic changes during fetal development.

Maternal smoking during pregnancy is associated with the downregulation of miR, miR, and miRa in the placenta Maccani et al. MiR and miR have thus been implicated as responsive mechanisms to cell stress Morales-Prieto et al. Across indirect epigenetic changes, per se , define only intergenerational epigenetic inheritance, which is inheritance from one generation to the next Pang et al.

AIE can be and has been considered, instead, a necessary but insufficient condition for transgenerational epigenetic inheritance, at least per its canonical definition Skinner, Many experiments have been performed to prove some form of epigenetic inheritance in the past two decades. We report several examples below. Rat malnutrition impairs cognition in offspring Galler and Seelig, A low-protein diet over 10 generations produces even more severe cognitive deficits, which are evident after two generations, on returning to a regular diet Stewart et al.

Dunn and Bale have demonstrated that a maternal high-fat diet in mice increases body size and insulin sensitivity, which endure until the second generation; these effects nearly vanish in the F3 generation, despite the alterations in body size being observed solely in female offspring, suggesting an imprinting mechanism.

Parental addiction in rodents alter the sensitivity of offspring to drugs, eliciting adaptive counterregulatory responses Byrnes et al. Environmental exposure to vinclozolin, an endocrine disruptor that is commonly used as an agricultural fungicide, increases sensitivity to stress—namely, anxious behavior—in the F3 generation Crews et al.

At the molecular level, several abnormalities have been observed, such as DNA methylation in the male testis of F1 animals, which impairs spermatogenic capacity Anway et al. Fetal exposure to alcohol or vinclozolin heightens the sensitivity of newborn rats and their two ensuing generations to stress Govorko et al. Chronic, unpredictable traumatic experiences in early postnatal life alter social recognition, and chronic social instability in adolescence disrupts social interactions across three generations; these properties are transmitted through the germ cells of male and female mice, despite the former failing to express any symptoms Franklin et al.

Postnatal trauma elicits depressive-like behaviors that are evident for up to three generations, even after crossfostering Franklin et al. These changes are associated with altered DNA methylation levels in the brain and sperm and have been interpreted as a change in the stress response.

Repeated social stress in male mice during adolescence increases behavioral despair and anxiety in their offspring Dietz et al. In a study by Yao et al.

These abnormalities were associated with the upregulation of miRb and downregulation of miR Paternal chronic stress sensitizes F1 animals to stress and evokes depressive-like behaviors, in association with altered miRNA expression in sperm in F2 Morgan and Bale, A similar stress paradigm was applied to demonstrate that paternal stress alters sperm miRNA levels, perhaps mediating the disruptions in stress response in subsequent generations Rodgers et al.

The authors suggested that miRNA expression in sperm silences maternal gene expression and epigenetically alters the developmental fate of subsequent generations. In Short et al. Further, the paternally imprinted gene Igf2 was overexpressed and underexpressed in the hippocampus of males and females, respectively. F2 offspring exhibited lower levels of anxiety, but only males developed a depressive-like phenotype.

The levels of miR, miR and miRb were altered in the sperm of F0 males, and thus, they were regarded as putative mediators of the epigenetic effects of corticosterone across generations. Notably, environmental enrichment reverted some of the adverse outcomes of the stress that was experienced by grandparents Leshem and Schulkin, and improved memory in subsequent generations Arai et al. In addition to the effects of negative environments across generations, recent studies have begun to examine those of positive conditions.

Enhanced cognitive stimulation and physical activity reduce the response to adult stress, but only recently have the transgenerational effects of enrichment of the paternal environment on the offspring been evaluated.

Anxiety-like and depression-like behaviors and biomarkers of the stress response have been assessed in F1 and F2 descendants from male mice that have been exposed to environmental enrichment F0. A sex-dependent effect on stress responsivity emerged in the F2 generation Yeshurun et al. Short et al. Direct proof of transgenerational epigenetic inheritance in humans remains lacking van Otterdijk and Michels, Nevertheless, there is notable indirect evidence i.

Male children who were exposed to intrauterine undernourishment during the 5-month Dutch famine occurring in — and their offspring developed obesity, glucose intolerance and coronary heart disease in adult life Painter et al.

In some cases, these symptoms were associated with altered levels of DNA methylation 60 years later Heijmans et al. Further, the risk of diseases is higher when gestational famine is followed by a calorie-rich diet later in life Schulz, Transgenerational transmission of trauma has been studied in the offspring of Holocaust survivors, combat veterans, and refugee families Vaage et al. A Norwegian longitudinal study on Vietnamese refugees reported a high risk of mental disease in F3 offspring, when grandparents were diagnosed with post-traumatic stress disorder on their arrival in Norway Vaage et al.

There is copious evidence of epigenetic changes in animal models, but this field must improve to generate stronger evidence and implement new techniques that could apply to human studies, in which direct and robust proof remains lacking.

We have compiled many studies and divided them by epigenetic type and research model Table 1. Table 1. Evidences of the three defined forms of epigenetic changes: direct epigenetics DE , within indirect epigenetics WIE and across indirect epigenetics AIE. How does epigenetic inheritance occur concretely?

Although several epigenetic processes have been considered to answer this question, given the wide range of this work, we will focus on two of the more extensively studied mechanisms: methylation and ncRNA. First-generation epigenetic mechanisms are centered on modifications to chromatin density—i.

These mechanisms depend on several enzymatic activities that effect acetylation, methylation and phosphorylation of histone tails primarily lysine, arginine and serine and their removal deacetylation, demethylation and dephosphorylation ; ATP-dependent chromatin remodeling proteins that actively and transiently modify nucleosomal structure ; and cytosine methylation Portela and Esteller, ; Cooper and Hausman, Although these processes might mediate epigenetic inheritance, methylation is the most well-understood mechanism regarding this matter Babenko et al.

DNA methylation is an enzymatic process by which a methyl group CH 3 is covalently bound to the fifth position of a cytosine residue 5-methylcytosine, 5mC to alter gene expression.

When methylation affects the promoter region, it is associated with gene silencing—the most well-known function of this mechanism; however, when it involves the transcribed region, it increases transcriptional activity Jones, DNA methylation is involved in many processes, particularly those that are important for early development, such as genomic imprinting, X-chromosome inactivation, and transposon silencing Smith and Meissner, The maintenance of methylation is crucial for ensuring the continuity of the structural and functional identities of somatic cells throughout cell division.

Thus, after each replication, the symmetry of the methylation pattern is restored Zhang et al. Although methylation patterns are stable, they can be erased by two mechanisms: active and passive demethylation. This subfamily of dioxygenases catalyzes the oxidation of 5mC to hydroxymethylcytosine 5hmC , 5-formylcytosine 5fC and finally 5-carboxylcytosine 5caC.

This conversion is the first step toward complete demethylation through two pathways. In the second route, 5fC and 5acC can be excised from DNA by thymine DNA glycosylase, and the resulting lesion is promptly repaired through the base excision repair BER pathway, generating an unmodified cytosine. Thymine DNA glycosylase and BER are also recruited when 5mC is deaminated to thymine by activation-induced deaminase, particularly in promoter regions during somatic cell reprogramming Seisenberger et al.

An overview of methylation and demethylation mechanisms is provided in Figure 3. Figure 3. Methylation and demethylation. Methylation is a regulatory process of gene expression, catalyzed by DNA methyltransferase enzymes, owing to the addition of a methyl group to the fifth position of a cytosine.

Methylation processes can be reverted by two mechanisms: passive demethylation due to loss of methylation across consecutive DNA replications; active demethylation mediated by ten-eleven translocation TET proteins. Maintenance and de novo methylation and active and passive demethylation are crucial for embryonic development and epigenetic inheritance. Gametes are completely demethylated and are remethylated after fertilization to erase all epigenetic marks that an individual accumulates over his lifespan.

However, this resetting process is impeded during early development, perhaps accounting for transgenerational transmission of these epigenetic footprints van Otterdijk and Michels, Elimination and restoration of methylation markers occurs in two steps Figure 4.

Immediately after fertilization, global demethylation is observed that erases methylation marks of the parental gametes through two sex-dependent mechanisms. First, the DNA in paternal pronuclei undergoes rapid, active demethylation that is mediated by TET3 proteins, which spare only imprinting control regions ICRs and certain retrotransposons, such as intracisternal A particles.

This process takes place at approximately the time of DNA replication and ends before the first cell division is completed. Then, the maternal genome is progressively demethylated through passive demethylation across subsequent cleavage steps Seisenberger et al. Consequently, the totipotency of the zygote is established and maintained across the first several cell divisions.

Figure 4. Biomarker reset. The elimination and restoration of methylation markers happen in two steps. A first, active demethylation takes place in parental gametes, right after fertilization. This process is mostly active—and therefore faster: it is completed by the first cell division—for paternally inherited genome, while maternal pronucleus is slowly demethylated by passive diffusion across replications.

This first global erasure of methylation marks spares only imprinted loci and some retrotransposons, and it is deemed to establish cellular totipotency.

After the implantation of the developing blastocyst, a first de novo methylation wave begins, driving the crucial process of cellular differentiation. Imprinting patterns are usually reestablished during this phase. The established patterns can be altered by direct or indirect experiences, particularly during gestation and right after birth.

The maternal factor Stella has been suggested to protect the maternal genome and paternal ICRs and intracisternal A particles from active demethylation. These regions undergo H3K9 a Stella binding site demethylation.

Moreover, inside of the oocyte and zygote, the DNMT1o isoform predominates and is more concentrated in their cytoplasm. In contrast, DNMT1 is the chief isoform in somatic cell nuclei but is scarce in the zygote. These differences in nuclear and cytoplasmic concentrations of DNMT1 isoforms account for global passive demethylation and might explain the maintenance of maternal ICRs Cardoso and Leonhardt, ; Seisenberger et al.

Nevertheless, recent studies suggest that active and passive processes govern the demethylation of the maternal and paternal genomes van Otterdijk and Michels, After the implantation of the developing blastocyst, the inner mass cells IMCs undergo a wave of de novo methylation, which drives their differentiation. A second wave of demethylation is initiated at the outset of gametogenesis: primordial germ cells experience demethylation that starts during their migration and spreads to ICRs Zhao and Chen, ; Wu and Zhang, After sex determination, gametogonia DNA is remethylated through a second de novo methylation step.

As argued above, the transmitted patterns can be altered by direct or indirect experiences, particularly during gestation and immediately after birth. It appears that epigenetic transmission might be possible when the second demethylation step is prevented, as in the case of genomic imprinting, which constitutes the strongest evidence for transgenerational epigenetic inheritance in mammals van Otterdijk and Michels, Correct repression of transcription of certain genes is crucial for a good developmental outcome.

A glitch during genomic imprinting, for example, can cause severe pathologies, such as Prader—Willi and Angelman syndromes, which are derived from the loss of nonimprinted paternal and maternal genes, respectively Cassidy et al. New-generation epigenetic mechanisms also incorporate factors that modify the genetic expression at the translational level, such as alternative splicing, RNA editing, and regulation by ncRNAs Cooper and Hausman, Recently, ncRNAs have been implicated in disease development and manifestation and in their epigenetic transmission Peschansky and Wahlestedt, Many genes are translated into ncRNA Liu et al.

What do these molecules do? As we will discuss below, many groups e. These two groups can be subdivided, depending on their genomic origin and biogenic activity. Whereas NATs primarily regulate the expression of the sense partner transcript, the activities of the other four classes remain unknown, but they are likely to include transcriptional regulation, RNA stability, and the recruitment of protein complexes and other subcellular elements.

PiRNAs are usually composed of 26—30 nucleotides and can silence the transcription of target RNAs, promoting the trimethylation of histone 3 lysine 9 H3K9me3 , a marker of inactive chromatin, by a histone methyltransferase Luteijn and Ketting, The function of endo-siRNAs is not well understood, but it appears to require extensive sequence complementarity to repress genes Okamura et al. Our understanding of the processes that generate mature small ncRNAs is patchy. Only the biogenesis of miRNAs has been determined.

Their genetic loci can be subject to epigenetic regulation, like protein-coding genes, becoming susceptible of environmental influences; further, they govern gene expression Peschansky and Wahlestedt, ; Szyf, Recently, the miRNA expression patterns in placental Gu et al.

As discussed, fetal programming alone does not account for epigenetic transmission, unless we include the effect of previous environmental factors i. As pointed out by Bohacek and Mansuy , germ cell reprogramming could be a key mechanism of transgenerational epigenetic inheritance. Epigenetic changes in germ cells arise and are maintained throughout methylation and acetylation, but miRNAs, particularly those in sperm, appear to have important functions e. Conversely, global suppression of miRNA paired with the functional predominance of endo-siRNAs has been observed in mature oocytes and during early embryonic development Ma et al.

Their function in the latter phases of zygote development remains unknown, but as we will discuss, there is evidence of the role of miRNAs in the regulation of oocyte function Tang et al.

However, much work is needed to determine their functions. Epigenetic inheritance has been suggested to be governed by the crosstalk between canonical epigenetic mechanisms primarily methylation and the regulation of gene expression by ncRNAs at the translational and transcriptional levels, as proposed by several groups e.

Although there is no direct evidence of the exact mechanisms that are involved, some hypotheses can be introduced. The most notable—albeit more obscure and less extensively studied—function of ncRNAs could be to establish the intrauterine environment and gametes before conception, producing new, stable epigenetic marks, such as methylation, that are stably maintained at least across one generation AIE.

Further, the direct transmission of ncRNAs through paternal sperm or fluids and maternal germ cells could intervene in setting epigenetic patterns.

Conversely, the presence or absence of molecular tags such as UHRF1 could influence the expression of crucial ncRNAs during the first or second stage of demethylation, also sex-dependently Figure 4. These models are only some of the hypotheses that our current understanding allows, and surely overlooks other less well-understood processes, such as histone modification and retention, DNA hydroxymethylation, and chromatin remodeling.

These mechanisms are suggested to be relevant to epigenetic inheritance and subject to some form of regulation by ncRNAs, necessitating further evidence of their implication Babenko et al.

As pointed out by many groups, Dunn et al. This model is consistent with the growing body of literature above see Yeshurun and Hannan, for an exhaustive review. These effects have been studied widely in terms of the transmission of stress sensitivity in animal and human models see above.

For example, in rodents, stressing the mother during pregnancy and the father before mating can effect alterations in stress sensitivity in the offspring, manifesting at the molecular and behavioral levels Dunn et al. Paternal experiences can induce changes in the sperm that impact, for example, the HPA axis in progeny, their cognitive abilities, and their cellular and molecular processes Yeshurun and Hannan, Many authors posit that this type of epigenetic transmission of environmental information determines the miRNA composition of paternal sperm, which is sensitive to environmental changes e.

According to some groups, miRNAs mediate this form of transgenerational communication, based on their ability to regulate the remethylation that occurs during gamete maturation and fertilization Sinkkonen et al.

As discussed, paternal influence is not limited to sperm: it can contribute during pregnancy as a stimulus that influences the maternal environment of the fetus Todrank et al. Similarly, oocytes could transmit epigenetic marks of maternal experiences that occur before pregnancy.

We should consider that the germ cells in both sexes can be modified epigenetically during fetal development and after birth, throughout life despite little evidence to support this hypothesis concerning oocytes. The best evidence of the importance of maternal miRNA, however, is the discovery of a paternally imprinted 14q32 domain, which allows the exclusive maternal expression of approximately 40 miRNAs Seitz et al.

The first studies on epigenetic forms of transmission focused on the effects of maternal care on the early stages of life, later considering nongenetic forms of developmental programming of fetal development during pregnancy.

A practical problem arose, however: because mothers carry their children for 9 months and then care for them, it was difficult to distinguish between pre-, peri- and postnatal epigenetic effects. Thus, several groups concluded that the paternal contribution should be considered. In many species, the only contribution of males is their sperm, which does not interfere with the gestational and postnatal periods.

This approach has been useful in demonstrating epigenetic inheritance, but it does not allow one to frame the entire landscape of mechanisms of epigenetic transmission: excluding maternal pregestational function because it is intractable for study fails to demonstrate that it does not exist or that it is irrelevant. Most of the literature has focused on the paternal role in mediating AIE see Yeshurun and Hannan, , whereas maternal function has been neglected. The drawback of many models of epigenetic inheritance is that they do not allow one to distinguish and define paternal and maternal contributions simultaneously for every effector that mediates the transmission of a certain property, such as stress reactivity.

Stress vulnerability could result from the co-occurrence of maternal and paternal factors or show maternal or paternal preference, depending on the effector e.

Further, the prevalence of maternal and paternal contributions could depend on environmental conditions that could bring about, for example, paternal prevalence when the father is stressed or the predominance of maternal contribution under baseline conditions. Bohacek and Mansuy have suggested methodological practices that could mitigate the effects of the intervenient factors above. For example, artificial insemination or in vitro fertilization IVF should allow one to exclude the effects of seminal fluid and interactions during mating.

The disadvantage of these techniques, however, is that they require superovulation a fertilization procedure that increases the number of oocytes that are produced and the use of culture for IVF and chemical manipulation, which could alter ecological epigenetic programs. Intrauterine and maternal care could be controlled for through embryo transfer and crossfostering, respectively. The function of a specific effector, independent of its parental origin, could be tested by injecting molecules directly into a zygote Bohacek and Mansuy, or germ cells.

When the gene of interest is missing from birth, several changes are developmentally established, which are nonspecific and stable. The inconvenience of these models is that the effects of manipulating a certain gene result from a series of functional and structural adaptations throughout development.

An alternative solution is to use conditional models and other genetic engineering techniques, as reviewed by Issler and Chen By combining a KO model with a double crossbreeding procedure, once behavioral profiles have been defined for the WT and KO lines, it should be possible to determine whether a certain gene is subject to genomic imprinting, simply by observing the offspring phenotypes; if it is, two divergent behavioral tendencies should be observed.

However, imprinting is not an all-or-nothing phenomenon, and ambiguous results could be clarified with other techniques that measure allelic expression directly see Rienecker et al. This methylation turns the gene off, stopping the FMR1 gene from producing an important protein called fragile X mental retardation protein. Loss of this specific protein causes fragile X syndrome. Although a lot of attention has been given to the CGG expansion mutation as the cause of fragile X, the epigenetic change associated with FMR1 methylation is the real syndrome culprit.

Fragile X syndrome is not the only disorder associated with mental retardation that involves epigenetic changes. Because so many diseases, such as cancer, involve epigenetic changes, it seems reasonable to try to counteract these modifications with epigenetic treatments.

These changes seem an ideal target because they are by nature reversible, unlike DNA sequence mutations. The most popular of these treatments aim to alter either DNA methylation or histone acetylation. Inhibitors of DNA methylation can reactivate genes that have been silenced. These medications work by acting like the nucleotide cytosine and incorporating themselves into DNA while it is replicating. Drugs aimed at histone modifications are called histone deacetylase HDAC inhibitors. Blocking this process with HDAC inhibitors turns on gene expression.

Caution in using epigenetic therapy is necessary because epigenetic processes and changes are so widespread. To be successful, epigenetic treatments must be selective to irregular cells; otherwise, activating gene transcription in normal cells could make them cancerous, so the treatments could cause the very disorders they are trying to counteract.

Despite this possible drawback, researchers are finding ways to specifically target abnormal cells with minimal damage to normal cells, and epigenetic therapy is beginning to look increasingly promising. Egger, G. Epigenetics in human disease and prospects for epigenetic therapy.

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