The study of heritable genetic information that is separate from the sequence of bases on DNA is known as epigenetics. This is a rapidly expanding field of study involving chemical changes in the chromosomes, and associated proteins, that can directly affect the phenotype of a eukaryotic cell via changes in gene expression. The systems associated with epigenetics and epigenetic changes of the eukaryotic genome are influenced by many factors. They can be inherited, environmentally altered or a product of stochastic events. Epigenetics has profound implications on genetic disease, with minor defects in epigenetic mechanism causing severe disease phenotypes. Due to the ability of epigenetic changes to alter the gene expression profile of a cell there has been much research into possible epigenetic drug therapies to combat epigenetic and non-epigenetic diseases. This paper reviews the mechanism of epigenetics and their relations to disease and possible therapies.
What is Epigenetics?
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Epigenetics is the field of study that encompasses heritable information associated with the eukaryotic genome that is separate from sequence of bases present on the DNA. Epigenetics can be described as the process by which a phenotype is altered, due to changes in gene expression, that are caused by a mechanism other than a change in the DNA sequence. These changes can be heritable and relatively stable, lasting much longer than most DNA mutations (Calvanese et al. 2009). Epigenetic changes have been reported as stable, but they are also controlled by varying factors which include environmental, physiological and pathological factors (Calvanese et al. 2009) therefore they are subject to change during a cells lifetime. Epigenetic changes are one of the major factors in determining cell differentiation during early development. Diseases that are associated with epigenetic changes can be both hereditary (associated with developmental defects) and show late-onset phenotypes (due to interactions between the epigenome, the genome and the environment) (Feinberg 2007).
Mechanism of Epigenetic changes
There are many mechanisms that contribute to epigenetic changes in the eukaryotic genome, but two main types dominate and hence the majority of work has focused on these two. These modifications are DNA methylation and histone modifications.
Histones can be modified by methylation, acetylation, phosphorylation, sumoylation, proline isomerisation and ubiquitination (Calvanese et al. 2009). Nucleosomes act as general transcriptional repressors, causing the need for activators at all eukaryotic promoters. Histone acetylation reduces the affinity of the nucleosomes for DNA by acetylating the lysine residues of the histone tails. This reduces the positive charge of the histones and hence reduces its affinity to DNA (which is positively charged), overcoming the general repressive action of nucleosomes and allowing activation of transcription. Sin3 and NuRD are examples of proteins, which are known as histone deacetylases (HDACs). HDACs act as transcriptional repressors by inhibiting and reversing histone acetylation. Proteins with HAT activity (Histone Acetyl Transferase activity) acetylate histones, and therefore act as transcriptional activators.
Certain repressors (e.g. RB protein) recruit histone methyltransferases, which methylate histones causing the DNA to be repressed due to condensation. Upon methylation histones recruit silencing proteins (e.g. HPI) that help spread the methylation throughout the chromatin, causing widespread repression. DNA methylation is the process by which a methyl group is added to the aromatic ring of a DNA base. This is restricted to the 5-carbon of the cytosine ring of a CpG dinucleotide in mammals (Calvanese et al. 2009). Calvanese et al. reported that approximately 5% of cytosine bases are altered to 5-methylcytosine in higher eukaryotes, and that the CpG dinucleotide is highly under-represented in the eukaryote genome. There are certain areas in the eukaryotic genome with a distinctly high proportion of the CpG dinucleotide. These areas are known as CpG islands, and are found in approximately 40% of promoters of human genes (Calvanese et al. 2009).
Two types of methylases in higher eukaryotes methylate these promoter regions. Hemi-methylases are one class, they act as maintenance methylases by retaining the methyl group, which has already been added to the cytosine during DNA replication. These hemi-methylases keep the pattern of gene methylation constant through the organism lifetime, and allows accurate inheritance of the methylation profile. The other class of methylase (as of yet unknown) is defined by a process, yet to be fully described, by which a cytosine base is to be methylated in the first place.
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Eukaryotes possess methyl-CpG binding proteins (e.g. MECP2), which recruit HDACs. Once the histones are deacetylated they become methylated a specific positions. This methylated DNA structure in its active form recruits a group of silencing proteins, which inactivate the gene by chromosome condensation to form heterochromatin. DNA methylation is the mechanism of X-chromosome inactivation and imprinting effects (Boks et al. 2009). The gene may then be reactivated if the chromosome is demethylated, this can be achieved by many processes.
Mutation or inactivation of the methylase gene will silence the methylase effects and activate genes, which have been repressed. This would be the classical way to reactivate genes, which have been inactivated by methylation. There are drugs which have been developed (e.g. 5-azacytidine and 5-aza-2ââ‚¬â„¢-deoxycytidine) which can be incorporated into DNA, but are unable to be methylated. This leads to activation of gene expression, as the repressive methylation pattern cannot be sustained on the DNA. 5-azacytidine is currently undergoing drugs trials for treatment of myeldysplastic syndromes (MDS) (from lectures given by Dr Steve Minchin).
The environment has been implicated in targeting the epigenome of an individual. Heavy metals can disrupt DNA methylation patterns and chromatin formation due to disruptive effects on DNA binding for many classes of proteins. DNA methylation can also be altered anti-androgenic and oestrogenic toxins, which result in decreased male fertility. These epigenetic changes are stable, as they can subsequently be inherited (Feinberg 2007).
It is not just random environmental factors that can affect the epigenome, dietary choices have also been implicated. Diets which are deficient in folate and methionine lead to disruption in imprinting of IGF2 (Waterland et al. 2006). This dietary deficiency disrupts epigenetic mechanism because both folate and methionine are required for normal synthesis of S-adenosylmethionine. This compound is the methyl donor for methylcytosine, and without it cytosine is unable to become methylated in a cellular DNA complex.
Some epigenetic changes, which are environmentally or randomly induced, can be maintained in the epigenome beyond the first generation and passed on to offspring. This may still occur even when the original conditions, which caused the epigenetic change, are not present (Harper 2005). Therefore we can state that epigenetic changes do not only affect cell differentiation in one generation, but affect the germ cells and hence subsequent generations as well. For example Anway et al. (2005) found that exposing pregnant rats to endocrine disruptors during gestation caused the male offspring of these mothers to have decreased spermatogenesis. This caused an increase in infertility rates. Anyway et al. (2005) observed these changes in nearly all the males tested down to the fourth generation. This was attributed to altered patterns of DNA methylation in the germ cells.
Association with disease
Mutations in the genes for the co-activators SWI/SNF, which remodel DNA in an ATP dependent manner, have been linked to cancers. SWI/SNF reduce the affinity of histones for DNA, further loosening the chromosome structure, allowing active gene expression of many genes. SWI/SNF often work in conjunction with epigenetic factors, and interact with HDACS and methylases during transcription initiation. Inactivation of SNF5 causes malignant rhabdoid tumours, a cancer of the kidney found in children typically less than 2 years old. Tumour suppressor genes are often epigenetically repressed, normally due to methylation of the CpG islands in the promoter region of these genes. Rodenhiser & Mann (2006) found 26 cancers associated with hypermethylation and/or hypomethylation of DNA.
Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease found in humans. It creates some of the epigenetic alterations that are seen is the normal aging phenotype. For example there is a decrease in histone H3 trimethylation on lysine 27, and an increase in the trimethylation of histone H4 lysine 20 (Calvanese et al. 2009). Angleman Syndrome and Prada-Willi Syndrome, which are neurodevelopmental disorders, have been associated with changes in imprinting and epigenetic modifications (Masterpasqua 2009). Both are due to silencing of part of a region of DNA located on chromosome 15, although the phenotypes are very different (Masterpasqua 2009).
Monogenic epigenetic diseases can be put in one of two classes. In the first class there are genes that are regulated epigenetically, for example imprinted or diseases affecting the whole epigenome. These can be modifiers of methylation or acetylation (Feinberg 2007). Beckwith-Wieldemann Syndrome is a monogenic epigenetic disease that affects genes that are regulated epigenetically. This disease is characterised by pre-natal overgrowth amongst other developmental malformations and cancers (Feinberg 2007). Patients suffering from this disease show defects in imprinting of two subdomains on 11p15. H19/IGF2 (imprinted, maternally expressed, untranslated mRNA/insulin-like growth factor 2) is the first, it is methylated on the parental allele, but not on the maternal. The second subdomain constitutes many domains (p57KIP2, TSSC3, SLC22A1, KvLQT1 and LIT1), the subdomain being methylated just upstream of LIT1 on the maternal, but not the paternal allele (Feinberg 2007). Small deletions in these regions cause Beckwith-Wieldemann Syndrome.
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The second class of epigenetic diseases involves genes involved in epigenetic regulation of other genes. For example mutations of the methyl CpG-binding protein 2 (MeCP2) gene, encoding a methylated DNA binding protein (known as Rett Syndrome) causes disruption of neurodevelopment in later childhood and is ultimately an autism spectrum disorder (http://allpsych.com/disorders/dsm.html).
Due to the increased understanding of the epigenome, drugs targeting epigenetic disruptions are currently being trailed. Mack (2006) discusses two classes of epigenetic modifying agents, which are currently being trailed for clinical treatment of cancers, for example the treatment of myelodysplasia.
Epigenetic changes are vital for the correct development of eukaryotic cells and their subsequent differentiation. Although epigenetic changes are an important part of the cells genetic machinery, it underlines another area of genetics with potential to be disruptive to the cell if it is not correctly maintained. There are many different types of epigenetic changes, ranging from DNA methylation to histone acetylation, all contributing to build a profile of gene expression that is unaffected by the sequence of bases on the DNA. This allows for much finer control of gene expression and ultimately the phenotype of the cell than if it was left to the sequence of DNA alone.
Although recent research has implicated environmental factors in epigenetic changes (such as nutritional supplements, low dose radiation and exotic chemicals), the majority of epigenetic changes are not solely environmentally controlled.
Despite the fact that most epigenetic changes are not especially due to environmental factors, epigenetic changes are actually a support for the Lamarckism theory of evolution. This theory stated that an intrinsic driver caused evolution of certain traits, with the classical example being the lengthening of the giraffeââ‚¬â„¢s neck to reach richer food sources, which were higher up. Therefore epigenetics is a molecular mechanism for Lamarckism. Although this does not prove the theory, it does add more potency to the argument, increasing speculation on the matter.
It is now understood that stochastic events can have a profound effect on the phenotype of a eukaryotic cell. They can be cumulative (due to being heritable) and recent evidence shows rapid selection for certain stochastic events in response to environmental pressure (Bjornsson et al. 2004).
Even though epigenome targeted drugs are being trialled, there is still a long way to go before the drugs may become widely available. The main problem with an epigenetic drug is that it may enhance or silence a large variety of genes whilst affecting its target gene. This may cause even more severe diseases and disorders, or possibly pass on an unfavourable epigenetic profile to the progeny, which is a temporary fix, possibly leading to worse problems in the future.
(Bjornsson et al. 2004; Mack 2006; Waterland & Jirtle 2003; Waterland et al. 2006; Feinberg 2007; Anway et al. 2005; Harper 2005; Masterpasqua 2009; Rodenhiser & Mann 2006; Boks et al. 2009; H et al. n.d.; Calvanese et al. 2009)