Principles of epigenetics

INTRODUCTION — Epigenetic changes are heritable changes that alter gene expression without changing the primary DNA sequence. The implications of these changes are wide-ranging and impact many aspects of normal development, disease pathophysiology, and therapies for cancer and other conditions.

This topic provides an overview of epigenetics concepts and examples of their relevance to disease mechanisms and management for the practicing clinician. Related concepts are discussed in separate topic reviews.

●Glossary of terms used in genetics – (See "Genetics: Glossary of terms".)

●Genetics concepts and mechanisms of genetic disorders – (See "Basic genetics concepts: DNA regulation and gene expression".)

●Chromosome regulation – (See "Genomic disorders: An overview".)

●Mechanisms of inheritance – (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)" and "Principles of complex trait genetics".)

●DNA sequencing methods – (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

TERMINOLOGY AND BASIC CONCEPTS — Every nucleated cell in the body contains the same DNA sequence, which carries the organism's entire genome and includes coding and non-coding regions of DNA. Despite having the same genetic code, cells from different tissues behave very differently. These differences are not explained by differences in genome sequence, but rather are created by additional layers of regulation that determine which genes are expressed to create a cell-specific phenotype. Epigenetic regulation, which can increase or decrease the expression of genes without altering genomic sequence, contributes to this cell-type-specific variation.

Several terms and basic concepts apply to epigenetic regulation [1,2]:

●Epigenome – The epigenome consists of the entire epigenetic code across all of the cells in the body. It is contrasted to the genome in that the genome is constant across all cell types (with limited exceptions such as VDJ rearrangement in lymphocytes), but the epigenome varies from one cell type to another. In addition, while both are heritable, the epigenome can be reprogrammed, whereas the genome cannot. Reprogramming of the epigenome can occur during stages of normal development, in response to environmental exposures, in acquired disease states, and in response to medications that target epigenetic regulators. (See 'Types of processes that are regulated' below and 'Role of epigenetic changes in disease' below and 'Therapeutic uses' below.)

●Epigenetics – Epigenetics as a field of study refers to the analysis of changes that can occur on chromatin and DNA that are heritable and do not affect the primary DNA sequence. As noted in a 2018 review, epigenetics was originally conceptualized as interactions between genes and gene products that determine phenotype; only later was the key role of environmental influences appreciated [3].

●Epigenetic modification – An epigenetic modification (epigenetic change, epigenetic mark) is a chemical alteration to DNA or chromatin that does not affect the primary DNA sequence. Most definitions state that these changes are heritable from one cell to its progeny. Unlike changes to the genomic sequence, epigenetic changes are reversible.

Typically, epigenetic changes involve covalent attachment (or removal) of a small side chain (methyl group, acetyl group) to a DNA base or a histone protein. These changes alter the expression and regulation of genes and other DNA elements in a predictable fashion, although the specific implications of a modification (especially a histone modification) can be context-dependent; these have been referred to as the "histone code" [4-6]. These modifications and their consequences are discussed below. (See 'DNA methylation' below and 'Histone modifications' below.)

●Epigenetic regulation – Epigenetic regulation refers to the regulation of gene expression by epigenetic modifications. The modifications affect how easy it is for transcription factors, DNA polymerase, small RNAs, and other factors to physically interact with DNA. When the modifications are directly on the DNA, they are often located in the promoter or enhancer regions of the affected gene (ie, cis-regulatory elements) and alter access of the transcriptional machinery to the associated gene (eg, reduce or increase access to the gene). When the modifications are on histones, they affect how tightly the DNA is wrapped around the histone, which in turn affects how easy it is for these factors to access these DNA regions.

Some experts refer to the enzymes that create these DNA and histone modifications as "writers" and the enzymes that remove them as "erasers" (table 1) [7]. The proteins that recognize the marks are referred to as "readers"; there are a number of motifs in the reader proteins that can be used to recognize epigenetic modifications.

Epigenetic regulation is different from transcriptional regulation; transcription is controlled by a number of tissue-specific transcription factors. (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Transcription'.)

●Epigenetic epidemiology – Epigenetic epidemiology is a field of study that seeks to evaluate the effects of epigenetic changes in populations of individuals, such as cohorts of people who were exposed to conditions that might alter epigenetic regulation (eg, famines, toxins, shifts in dietary intake).

●Gene silencing – Silencing refers to reducing (or completely suppressing) expression of a gene. This can be achieved by the epigenetic mechanisms described below or by the actions of small RNAs that interfere with messenger RNA (mRNA) stability. Some experts consider these small RNAs, which may include small interfering RNAs (siRNAs) and microRNAs (miRNAs), to be epigenetic regulators as well.

●Imprinting – Imprinting refers to specific epigenetic modifications that are only added in either the male or female gametes (sperm and ova, respectively), subsequently resulting in parent-of-origin-specific gene regulation. Female-derived genes that are normally inactivated (ie, silenced in ova) are said to be maternally imprinted; male-derived genes that are normally silenced in sperm are said to be paternally imprinted.

•The classic clinical example is a region of chromosome 15 (the 15q11 gene cluster), which is differentially inactivated according to the sex of the parent of origin (parentally imprinted). The consequence of parental imprinting is that, if an individual inherits a pathogenic gene deletion affecting this cluster, the resulting phenotypic abnormalities differ depending on whether the mutation was inherited from the mother or the father. An inherited abnormality of this region derived from the mother results in Angelman syndrome, whereas an abnormality of this region inherited from the father results in Prader-Willi syndrome. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)'.)

•Imprinting is also responsible for differences in offspring that arise from interspecies mating of animals. As an example, the offspring of a male horse and a female donkey is a hinny (which has a thicker mane), while the offspring of a female horse and a male donkey is a mule (which has longer ears) [8,9].

Imprinting is responsible for some apparent deviations from classical Mendelian inheritance, as described separately. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)

●Heritability – Heritability is a feature included in most definitions of epigenetic modifications. The heritability of epigenetic changes refers to conserved changes from one cell division to another. In practical terms, the histone modifications may be removed during mitosis and added back in daughter cells, resulting in preserved information about the change [10]. Conservation of DNA methylation is coupled to DNA replication because DNA methyltransferases (DNMTs) interact with the replication machinery [11].

OVERVIEW OF REGULATION — Epigenetic regulation can be thought of as an additional layer of gene regulation beyond the DNA sequence that is more malleable and, because it is combinatorial and can result in a larger variety of outputs, is potentially more extensive than genetic regulation.

Types of epigenetic marks — Broadly speaking, there are two main forms of epigenetic modifications: those that directly modify DNA (ie, DNA methylation) and those that modify DNA-binding proteins (ie, histone modifications). Modifications can affect individual sites on or around a gene, exerting local regulatory effects, or they can affect larger regions of chromatin. The latter, which can span several megabases, help organize chromatin into genomic compartments in what is referred to as "higher-order" chromatin structures.

DNA methylation — Methyl groups can be added or removed from DNA, often in the promoter and enhancer regions of genes (figure 1).

●DNA methylation – DNA methylation involves addition of a methyl group (CH₃) to carbon 5 in a cytosine base to create 5-methylcytosine. In mammalian DNA, DNA methylation occurs almost exclusively at cytosines. Common sites for DNA methylation include promoter or enhancer regions of the affected gene (ie, cis-regulatory elements). Chromatin-regulatory proteins (eg, MeCP2, MBD2) bind to the methylated cytosines and reduce access of the transcriptional machinery to the gene, creating domains of repressed chromatin [12]. As a result, the consequence of DNA methylation in a gene promoter is often to prevent transcription of (ie, to "silence") that gene.

•In somatic cells, cytosine methylation occurs predominantly on cytosines that are part of a CpG dinucleotide (cytosine-phosphate-guanine)

•In embryonic stem cells, up to one fourth of cytosine methylation occurs on non-CpG cytosines

•In cancer cells, cytosine methylation is almost exclusively on cytosines in CpG dinucleotides

The enzymes that catalyze DNA methylation are referred to as DNA methyltransferases (DNMTs). DNMT3A and DNMT3B are responsible for creating new methylation marks and are therefore referred to as "de novo DNMTs." The heritability of DNA marks is maintained by another DNMT (DNMT1) during cell division. DNMT1 is coupled to the replication machinery. During S-phase of the cell cycle (DNA replication), the methyl group remains on the template (ie, the original) DNA strand, and this is copied to the new strand by DNMT1, thus maintaining the methylation symmetry across the CpG dinucleotide in the newly synthesized DNA.

●DNA hypomethylation – DNA hypomethylation involves removal of one or more methyl groups from cytosine bases, which may activate expression of a gene that was previously silenced; lack of methylation permits a more open chromatin configuration that facilitates transcription [12]. The term hypomethylation is used rather than demethylation because a few methyl groups may remain. Removal of methyl groups from DNA requires several steps, catalyzed by the TET proteins, referred to as methylcytosine dioxygenases, which get their name from the chromosome ten-eleven translocation seen in some myeloid malignancies [13]. (See 'Cancer' below.)

●DNA hypermethylation – DNA hypermethylation involves addition of more methyl groups to a gene or group of genes.

Histone modifications — Histones are proteins that form a multi-subunit core (often depicted as a disc) around which DNA can be wrapped to form a nucleosome; this is the first level of DNA compaction needed to assemble linear DNA into highly compacted chromosomes. Although the DNA in chromosomes is tightly packaged, it is wrapped in such a way that individual genes can be accessed through localized unwinding.

There are several modifications on histones, including methylation, acetylation, ubiquitylation, phosphorylation, and others [4-6]. These marks are often placed on the unstructured amino terminal "tails" of histone proteins (figure 1). The histone core is removed from the DNA during cell division; when histones are replaced following cell division, the enzymes also replace the histone modifications.

●Histone methylation and demethylation – Histone methylation involves addition of methyl groups (CH₃) to the amino acid lysine (designated as K), often in the histone tail; more than one lysine can be methylated on the same histone protein. The enzymes that catalyze histone methylation are referred to as histone methyltransferases; the enzymes that remove the methyl groups are referred to as histone demethylases.

●Histone acetylation and deacetylation – Histone acetylation refers to addition of an acetyl group (CH₃CO) to a lysine in a histone protein. The enzymes that catalyze histone acetylation are referred to as histone acetyltransferases (HATs). The enzymes that catalyze removal of an acetyl group from a histone are called histone deacetylases (HDACs). For the most part, these are metal-dependent enzymes that contain zinc in their catalytic site [14].

Histone deacetylation is common in certain malignancies, and inhibition of HDACs is used in certain cancer therapies. (See 'Cancer therapy' below.)

Histone modifications may alter the affinity of the histone proteins for DNA, or they may result in recruitment of other proteins that affect chromatin compaction. The consequences of histone modifications for transcription depend on the specific combinations of modifications. The modifications are named by specifying the histone subunit, the specific amino acid modified, and the type of modification. As examples:

●Modification associated with active transcription include histone 3 lysine 4 methylation (H3K4me3), histone 3 lysine 9 acetylation (H3K9ac), histone 3 lysine 36 methylation (H3K36me3), histone 3 lysine 79 methylation (H3K79me), and histone 4 lysine 20 acetylation (H4K20ac).

●Modifications associated with silencing and repression include histone 3 lysine 27 methylation (H3K27me3) and histone 3 lysine 9 methylation (H3K9me3).

Higher-order chromatin modifications — Chromatin is a complex structure of DNA, RNA, and associated regulatory proteins, all compactly packaged to create higher-order structures. Epigenetic modifications that affect larger topologic regions of chromatin can influence the expression of multiple genes simultaneously [3]. Examples of these types of higher-order chromatin structures include [15-17]:

●Sections of DNA packaged around nucleosomes with large numbers of histones containing dimethylated lysines, referred to as LOCKs (large organized chromatin lysine [K]-9 modifications)

●Regions of DNA associated with the filamentous nuclear lamina, referred to as LADs (lamina-associated domains)

●Three-dimensional organization of the chromatin into functional domains, referred to as TADs (topologically-associating domains)

Changes affecting these higher-order chromatin regions have been observed in differentiation (eg, transitions from embryonic stem cells to specialized somatic cells) and in certain cancers.

Types of processes that are regulated — Unlike genetic information, which is constant in nearly every cell (with the exception of lymphocytes that undergo VDJ rearrangement) throughout the life of the individual (unless a somatic mutation occurs), epigenetic information has great plasticity and can be altered depending on the cell type and developmental stage. As a result, epigenetic modifications mediate the differentiation of cells and adoption of different cell fates, which ultimately allows the complexity needed for normal functioning.

Some of the physiologic examples of epigenetic regulation over the life course include the following:

●X-chromosome inactivation – Genes on the X chromosome are present in two copies in the female and one copy in the male. In females, somatic cells undergo X-chromosome inactivation (also called X-inactivation or lyonization); the selection of which X chromosome gets inactivated (maternally derived or paternally derived) is random. Skewed X-inactivation is responsible for variable disease courses in women who are heterozygous for certain mutations (eg, hemophilia, hereditary nephritis, chronic granulomatous disease). Mechanisms of X-chromosome inactivation include silencing by the long non-coding RNA (lncRNA) Xist and methylation [18,19].

The inactivated X chromosome becomes a Barr body from which few to no genes are expressed (see "Genetics: Glossary of terms", section on 'X-inactivation'). Barr bodies are visible in a small proportion of neutrophils on the peripheral blood smear of a female.

●Cellular differentiation – Cells differentiate following fertilization to control embryologic development via tightly controlled steps in epigenetic regulation. Epigenetic changes play a role in stem cell programming as well as the differentiation of somatic cells into the specialized cells of the organ in which they reside.

●Response to the environment – In some cases, environmental changes result in adaptive epigenetic changes. Examples include caloric intake, stress, and toxin exposures [12]. These responses have been likened to immunologic memory, in that both processes can be induced, may persist for years to decades, may undergo selection pressure and amplification, and may be adaptive or maladaptive, depending on the characteristics of the environment in the future [12]. As a theoretical example, an epigenetic response to famine might improve chances of survival in a resource-poor setting but might lead to obesity and related disorders in a setting with unlimited access to calories. (See 'Environmental effects on health' below.)

The sirtuins are a family of proteins that regulate longevity, perhaps mediated by caloric intake. Among other functions, these proteins act as HDACs, and specific histone modifications have been described [20]. The compound resveratrol may act in part by increasing the affinity of the sirtuin SIRT1 for targets of deacetylation [20]. Additional information about the molecular basis of aging is presented separately. (See "Normal aging".)

Additional research into the biology of epigenetically regulated processes may be facilitated by reference human epigenomes such as those generated through the National Institutes of Health (NIH) Roadmap Epigenomics Consortium [21].

ROLE OF EPIGENETIC CHANGES IN DISEASE — Epigenetic marks can also contribute to developmental and acquired disorders [2]. Understanding of these effects is evolving, and the full impact of epigenetic changes in human disease is yet to be understood. Epigenetic effects on disease can be challenging to study because many genes may be affected, and it is challenging to determine which effects are causative. In addition, the effects can take years to develop, necessitating high-quality longitudinal data.

Developmental disorders — As noted above, Prader-Willi syndrome (PWS) and Angelman syndrome (AS) provide a classic example of disorders affected by parentally imprinted genes (see 'Terminology and basic concepts' above). Other, even rarer, examples include Russell-Silver syndrome and genome-wide uniparental disomies [22]. It has also been suggested that parent-of-origin effects may apply to complex disorders such as autism or schizophrenia [11]. Assisted reproductive technologies may have a small effect on global epigenetic marks, although clinically significant effects have not been demonstrated [22].

An example of specific genes that are targeted in PWS and AS are as follows:

●PWS results from paternal deficiency of the SNORD116-1 small nucleolar RNA (snoRNA) cluster

●AS results from absence of the maternally inherited copy of the UBE3A gene

Details of these syndromes and other developmental disorders in which epigenetic changes play a prominent role are discussed in separate UpToDate topic reviews. (See "Prader-Willi syndrome: Clinical features and diagnosis" and "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)'.)

Research on the effects of the prenatal environment on the development of certain conditions such as obesity is ongoing. (See 'Environmental effects on health' below.)

Environmental effects on health — As noted above, epigenetic changes in response to certain environmental exposures can be associated with adverse health conditions (see 'Types of processes that are regulated' above), although a causative role has not been definitively established. These exposures may occur prenatally or after birth, and the duration of their effects may last for decades or even into subsequent generations.

●Starvation, diabetes, and obesity – The availability of adequate nutrients to mothers during prenatal development causes distinct epigenetic changes. Individuals born during famines have also been observed to undergo distinct changes in DNA methylation patterns and histone modifications. These are referred to as transgenerational effects. A study of over 400 mother-father-infant triads also suggested that paternal obesity around the time of conception could influence birth weight and DNA methylation patterns in children, although the effect was small [23].

These changes may occur in response to naturally occurring epigenetic regulators such as butyrates that are induced during starvation [24]. One target of these changes is the insulin-like growth factor 2 gene (IGF2), which is maternally imprinted. In a study involving 60 individuals who were conceived during the Dutch Hunger Winter in World War II and studied 60 years later, CpG methylation was reduced compared with sex-matched sibling controls [25]. Numerous animal studies support the role for caloric availability in utero on subsequent metabolic effects in offspring. Starvation-induced epigenetic changes have been proposed to lead to "metabolic reprogramming" that is responsible for obesity later in life [26-28]. (See "Definition, epidemiology, and etiology of obesity in children and adolescents", section on 'Metabolic programming'.)

Conversely, intrauterine exposure to higher than normal levels of glucose (eg, due to maternal obesity or diabetes) can also lead to altered DNA methylation that predisposes offspring to develop diabetes and/or obesity [29].

Two large famines were associated with an increased incidence of schizophrenia in adulthood for individuals who were exposed to famine conditions in utero (during the first trimester of gestation) [3].

Certain epigenetic regulators require dietary nutrients as cofactors. Examples include folic acid, iron, and vitamin C. Depletion of these nutrients due to dietary restriction or other means may lead to altered epigenetic regulation, although the exact clinical consequences of specific nutrient deficiencies on gene expression are yet to be defined.

•Folic acid is a source of methyl groups used to form S-adenosylmethionine (SAM), the principal methyl donor for DNA methylation [12]. Seasonal changes in folic acid intake have been proposed to alter methylation patterns in developing fetuses that correlate with the season during which they were conceived [12].

•Iron chelation by fluoroquinolones has been proposed to account for epigenetic reprograming, leading to effects on collagen that may explain the increased risk of Achilles tendon rupture [30].

●Endocrine disruptors – Associations have been observed between ingestion of molecules from various sources (eg, pesticides, plastics, flame retardants, cosmetics) that interfere with normal hormone functioning and, as a result, can have adverse effects on normal maturation, reproductive health, and certain hormone-dependent cancers. These molecules have been termed endocrine disruptors. Exposure to some of these compounds has been demonstrated to cause abnormal DNA methylation and histone modifications, and evidence from animal models suggests a potential link to various reproductive effects and increased risk of certain cancers [31,32]. More studies of the causal links with human disease are needed. Additional information about the sources of endocrine-disrupting compounds and their clinical effects is presented separately. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Bisphenol A and other phenols' and "Endocrine-disrupting chemicals".)

●Smoke and air pollution – Cigarette smoke causes a variety of epigenetic changes, some of which have been hypothesized to contribute to smoking-related conditions including asthma, chronic obstructive pulmonary disease, and lung cancer [33-35]. A consistent effect related to cardiovascular disease and lung cancer associated with tobacco smoke exposure is methylation of the F2RL3 gene [36-38].

The Kinston Allergy Birth Cohort includes 560 individuals recruited prenatally who can be assessed for respiratory outcomes related to certain exposures, including cigarette smoke, air fresheners, and indoor mold [39]. Other studies have measured epigenetic changes associated with exposure to particulate matter from vehicular traffic, although the implications of these epigenetic marks for diagnosing or treating pollution-related disorders are unknown [40].

●Stress – Animal studies suggest that stressful experiences can produce epigenetic changes [12].

●Microbiome – The role of the microbiome in epigenetic changes is under investigation.

These changes may synergize with or oppose associated genetic changes and/or changes in cell signaling that are also induced by the exposures.

Cancer

General principles of epigenetic changes in cancer — All cancers are epigenetically abnormal, and some cancers share common epigenetic signatures. Just as epigenetic marks can give a stem cell or an early progenitor cell an immature phenotype with expanded potential to survive and replicate, epigenetic changes in cancer cells can promote similar properties, including immaturity, resistance to cell death, and high replicative potential. The epigenetic changes can include global hypomethylation and/or gene-specific promoter hypermethylation, as well as changes in histone methylation and acetylation [41,42]. The types of epigenetic abnormalities may differ and have not been identified in all cases. Some experts, including this author, suggest that alterations in the epigenome are a central feature shared by cancers derived from diverse tissues [3].

●Global hypomethylation can lead to the activation of oncogenes. As an example, hypomethylation of RAS oncogenes in many solid tumors was the first DNA methylation abnormality to be described in cancer [43].

●Promoter methylation is seen in virtually every type of tumor, and it affects many more genes than are affected by gene mutations (hundreds to thousands of genes per tumor). Promoter hypermethylation can lead to aberrant silencing of tumor suppressor genes. As an example, p16 is frequently hypermethylated in colon cancer.

●Loss of imprinting (LOI) on a normally silenced gene can also occur (see 'Terminology and basic concepts' above). As an example, LOI of the insulin-like growth factor 2 gene (IGF2) is common in Wilms tumor [41]. (See "Presentation, diagnosis, and staging of Wilms tumor", section on 'Genetics'.)

Epigenetic abnormalities are a hallmark of cancer, and while certain aspects of epigenetic deregulation such as those described above may frequently be observed across many cancers, each cancer type (and subtype) is characterized by specific patterns of alterations in epigenetic marks, which contribute to determining the biologic phenotype.

Hematologic malignancies — The epigenetic changes in hematologic malignancies have been well studied, and several genes that are commonly mutated in hematopoietic cells function in controlling epigenetic marks. Examples include:

●Genes that control histone modifications, such as MLL, EZH2, UTX, and ASXL1

●Genes that control DNA methylation, such as TET2, IDH1, IDH2, and DNMT3A

●Genes that control nucleosome position, such as SNF5, ARID1A, and PBRM1

●Genes that control three-dimensional chromatin organization, such as SMC1A, SMC3, STAG1/2, and RAD21

Pathogenic variants in these genes may be seen in both myeloid and lymphoid malignancies, as well as in clonal hematopoiesis of indeterminate potential (CHIP). In some cases, they may serve as useful biomarkers of prognosis and response to therapy [1,44,45]. (See "Acute myeloid leukemia: Molecular genetics" and "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)" and "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

Solid tumors — Epigenetic changes and DNA sequence variants in epigenetic modifier genes may also be seen in solid tumors. They may even be present in premalignant lesions and/or have therapeutic or prognostic significance in solid tumors.

As examples:

●Alterations in DNA methylation have shown prognostic significance in lung cancer [46]. In a cohort of smokers, promoter hypermethylation in several genes preceded development of lung cancer by months to years and were predictive of cancer development [47,48].

●Mutations affecting the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes play a role in the pathogenesis of malignant gliomas; these mutations, which are associated with increased DNA methylation, confer longer overall survival compared with non-IDH-mutated gliomas [49-51]. In high-grade gliomas (glioblastomas), hypermethylation of the DNA repair gene MGMT (O6-methylguanine-DNA methyltransferase) predicted for chemosensitivity [52]. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors" and "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'MGMT methylation status'.)

●A hypermethylation phenotype has been identified in some colorectal cancers. (See "Molecular genetics of colorectal cancer", section on 'Hypermethylation phenotype (CIMP+) pathway' and "Molecular genetics of colorectal cancer", section on 'Epigenetic alterations affecting mismatch repair genes'.)

●Global histone modification patterns have been shown to predict recurrence of prostate cancer [53].

Epigenetic patterns may also be used to predict response to specific types of cancer therapy, such as the chemosensitivity of high-grade gliomas with hypermethylated MGMT.

THERAPEUTIC USES — The epigenome is a therapeutic target in cancer and other conditions. One of the advantages of targeting epigenetic changes that differs from genetic changes is the reversibility of epigenetic marks, which translates to a greater potential for reprogramming.

A number of medical therapies have been developed that alter various types of epigenetic marks and may be therapeutically useful for manipulating gene expression. Most therapeutic applications and ongoing research focus on cancer treatment [14]. However, pilot studies are investigating possible roles in other conditions, as described below.

In addition to drugs that target enzymes that make or remove epigenetic marks, medications commonly known to act by non-epigenetic mechanisms may also have an epigenetic component. As an example, some studies of the mechanism of glucocorticoid action have demonstrated that suppression of inflammation may be mediated in part by the histone deacetylase HDAC2, as discussed separately. (See "Molecular effects of inhaled glucocorticoid therapy in asthma", section on 'Switching off inflammatory genes'.)

Drug classes

Hypomethylating agents — Drugs that inhibit DNA methyltransferases (DNMTs) result in reduced DNA methylation. Examples include the nucleoside analogues 5-azacytidine and decitabine. Since these drugs are incorporated into the DNA during replication, they may also trigger the DNA damage response, especially when administered at higher doses.

Histone deacetylase inhibitors — In contrast to histone methylation, which can be either repressive or activating, depending on the lysine modified, histone acetylation is always activating. Drugs that inhibit histone deacetylases (HDACs) result in increased histone acetylation, resulting in increased gene expression. Their structures are diverse and include non-peptide and peptide molecules; some of the peptides are cyclic [14]. Of interest, some of the HDACs in clinical use were isolated from bacteria, suggesting that they are likely to have biologic functions in these microorganisms.

HDAC inhibitors available for clinical use include the following:

●Butyric acid (also called butyrate) is a short-chain fatty acid (SCFA) that was the first compound identified as an HDAC inhibitor [54]. Butyrate and related compounds may be responsible for some of the epigenetic changes induced by starvation. (See 'Environmental effects on health' above.)

●Trichostatin A (TSA) is a natural product obtained by microbial fermentation. TSA is under investigation in disorders associated with increased cell proliferation such as systemic sclerosis (scleroderma).

●Romidepsin (also called depsipeptide) is a natural product HDAC inhibitor isolated from bacterial fermentation of Chromobacterium violaceum [14]. Romidepsin is used in the treatment of T-cell lymphomas.

●Valproic acid (the anti-seizure drug) inhibits HDACs in addition to its other roles in neurotransmitter modulation [54]. Valproic acid has been evaluated in various solid tumors and sickle cell disease (SCD).

●Panobinostat and vorinostat are HDAC inhibitors derived from hydroxamic acid [55,56]. Vorinostat is used in cutaneous T cell lymphoma. Panobinostat was withdrawn from the United States market due to lack of completion of confirmatory trials required as part of the accelerated approval in 2015.

A number of other HDAC inhibitors are under various stages of development [1,14]. A significant characteristic of the clinically available HDAC inhibitors is that they are not specific for histone deacetylases; they also inhibit other protein deacetylases (ie, enzymes that deacetylate non-histone proteins such as tubulin). However, these therapies generally appear well-tolerated despite potential effects on multiple organ systems. (See 'Potential adverse effects' below.)

Disease targets

Cancer therapy — As discussed above, epigenetic changes are a hallmark of cancer. (See 'Cancer' above.)

Several hematologic malignancies are treated with therapies that incorporate DNMT and/or HDAC inhibitors [42,57]. As examples:

●Hypomethylating agents are used in myelodysplastic syndromes and myelodysplastic/myeloproliferative overlap syndromes. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Hypomethylating agents' and "Treatment of high or very high risk myelodysplastic syndromes".)

●HDAC inhibitors are used in some individuals with lymphoid malignancies including multiple myeloma and Sezary syndrome. (See "Treatment of Sézary syndrome", section on 'Histone deacetylase inhibitors'.)

Studies are ongoing for other hematologic malignancies [42].

Hemoglobinopathies — In sickle cell disease (SCD) and beta thalassemia major, therapies that shift the ratio of gene expression from the beta globin gene (which carries the sickle hemoglobin mutation or thalassemic variant) to gamma globin gene (which lacks the disease-associated genetic changes and can pair with alpha chains to make fetal hemoglobin [HbF]) can greatly ameliorate the disease phenotype. Several approaches are under investigation that may work by increasing gamma globin gene expression, including DNMT inhibitors and HDAC inhibitors. Evidence for their efficacy and mechanism of action is presented separately. (See "Management of thalassemia", section on 'Epigenetic and JAK2 regulators'.)

Infection/inflammation — Epigenetic changes have been shown to play a role in viral infections, including human herpes virus 8 (HHV8) and human immunodeficiency virus (HIV), and small studies are testing valproic acid as a means to reduce latent HIV infection in individuals receiving antiviral therapies [54] (see "Human herpesvirus-8 infection", section on 'Pathogenesis'). Epigenetic therapies have also been proposed in inflammatory and fibrotic disorders such as systemic sclerosis (scleroderma) [58].

Neurologic and psychiatric disorders — Preliminary evidence has suggested that certain neurologic and psychiatric disorders may be subject to epigenetic regulation:

●Pathophysiologic studies of psychiatric disorders such as drug addiction, depression, and bipolar disorder may be associated with abnormal histone acetylation. (See "Unipolar depression: Genetics", section on 'Epigenetics' and "Bipolar disorder in adults: Epidemiology and pathogenesis", section on 'Epigenetics'.)

●Some epidemiologic data also suggest that Alzheimer disease risk may have an epigenetic component. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease".)

These observations have raised the intriguing possibility that HDAC inhibitors might be tested as therapies for these disorders [59]. Preclinical work and small pilot studies are testing the effects of adding HDAC inhibitors to existing therapies for psychiatric disorders including schizophrenia and cocaine addiction.

Potential adverse effects — Since most of the available drugs target enzymes with global effects, there may be adverse events related to changes in various organ systems. However, the drugs are well tolerated, and two decades of usage show they are safe with minimal side effects. Product information for the specific medication should be consulted.

As mentioned, some HDAC inhibitors may also block deacetylation of other proteins. HDAC inhibitors have been reported to cause electrocardiogram (ECG) changes, including prolongation of the corrected QT (QTc) interval, and/or to cause cardiac ischemia in some studies. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Histone deacetylase inhibitors'.)

SUMMARY

●Terminology and mechanisms – Epigenetic modifications involve changes (typically, addition or removal of a methyl group or other side group) to DNA or histones that alter gene expression without changing the primary DNA sequence (figure 1). DNA can be methylated on cytosine bases. Histones can undergo several modifications including methylation, acetylation, ubiquitylation, phosphorylation, and others. These changes are passed down from one cell to another (ie, they are heritable) and can be altered in response to developmental cues or environmental exposures. Examples of normal processes influenced by epigenetic changes include X-chromosome inactivation, normal cellular differentiation, and physiologic adaptations to environmental changes. (See 'Terminology and basic concepts' above and 'Overview of regulation' above.)

●Clinical implications

•Development – Prader-Willi and Angelman syndromes are a classic example of disorders affected by parentally imprinted genes (ie, genes that are silenced by methylation patterns that depend on the sex of the parent of origin). (See 'Developmental disorders' above.)

•Environmental exposures – Epigenetic changes in response to certain environmental exposures can be associated with adverse health conditions, although a causative role is challenging to establish, and much of the evidence comes from animal studies. Some of the best-characterized associations are with maternal caloric restriction (starvation) or caloric excess (eg, in diabetes) during gestation and obesity in offspring. Other examples include ingestion of endocrine-disrupting agents (eg, in pesticides, plastics, and flame retardants) with reproductive health and certain hormone-dependent cancers, inhalation of smoke and air pollutants with respiratory illnesses, and possible effects of stressful experiences. (See 'Environmental effects on health' above.)

•Cancer – Epigenetic changes in cancer cells or premalignant cells can promote stem cell or progenitor cell-like properties including immaturity, resistance to cell death, and high replicative potential. The epigenetic changes can include global hypomethylation and/or gene-specific promoter hypermethylation, as well as changes in histone methylation and acetylation. Several hematologic malignancies and solid tumors have been demonstrated to show epigenetic changes and/or mutation of genes that regulate epigenetic modifications. (See 'Cancer' above.)

•Therapeutics – Drugs that inhibit DNA methyltransferases or histone deacetylases (DNMT inhibitors and HDAC inhibitors, respectively) are used clinically in certain cancers. These drugs are also under investigation for treating hemoglobinopathies (eg, sickle cell disease, beta thalassemia major) because they appear to shift gene expression from beta to gamma globin and in turn increase production of fetal hemoglobin (HbF), which lacks the mutation. Use of these drugs for other disorders is under study. Adverse effects are numerous, but the drugs are generally well tolerated. (See 'Therapeutic uses' above.)