Epigenetics And The Medical Repercussions Biology Essay



The chromatin structure

In a eukaryotic organism, a chromosome consists of DNA bound to proteins, and the latter can be of the histone type (with many variants; Table 1) and non-histone type. The complex that is formed between DNA and protein is called chromatin. The DNA in chromatin is wrapped around cores of histones to form nucleosomes3. Specifically, each nucleosome consists of about 146 bp (base pairs) of DNA wrapped around an octamer of core histone (including two each of histone H3, H4, H2B and H2A)4. Additionally, two other types of variants of histone protein, histone H1 or H5, give extra stability to the nucleosomal arrangement.

Table 1: The five major classes of Histone proteins

Core histones

H2A, H2B, H3 and H4

Linker histones

H1 and H5

Initially, chromatin was thought to be an inert structure involved only in wrapping DNA into the small confines of the nucleus, but today research is showing that chromatin is more dynamic, especially when it comes to the activation and repression of gene transcription 5.

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Figure 1: Packing of DNA into a Mitotic Chromosome (Purves W. K. et al., Life: The Science Of Biology, W. H. Freeman & Co Ltd. (2003)).

When a region on a chromosome needs to be transcribed, the chromatin structure is unwound by various chromatin remodeling factors making the genes more accessible to be read out. Inactive genes are tightly wrapped. Regions on the chromosome where genes are actively transcribed are called euchromatin whilst regions were the chromatin structure is tightly condensed and hence the genes are inactive are called heterochromatin.

Defining epigenetics and contrasting it with genetics

Since when DNA was discovered to be the structure for heritable information, it was considered to be the only layer that codes such information within the chromosomes. But the picture started to change when certain patterns of inheritance in many organisms (see Table 2) could not be explained by the classical Mendelian way. The answer was later found to lie in a new layer that also encodes information within the chromosomes. This was the epigenome.

Table 2: Patterns of inheritance that could not be explained by the classical Mendelian laws

Position-effect variegation (PEV) in Drosophila

Mutable loci in maize

Controlling elements

Paramutation at the R locus in maize

Heritable change in cortical patterning of Tetrahymena

X-chromosome inactivation in female mammals

Mosaic expression of X-linked genes in women

Mating-type (MAT) switching in yeasts S. cerevisiae and S. pombe

Both DNA and histones are covered with chemical tags and the epigenome refers to these chemical tags that shape the physical structure of the genome. 'Epi' is derived from classical Greek meaning 'on top' because the epigenome forms a second layer on top of the genome. Indeed, the presence or otherwise of these chemical tags is being found to dictate the degree of condensation of the chromatin structure, i.e. the chemical tags are responsible for whether the chromatin template with its genes is tightly wrapped and so inaccessible for transcription or whether the chromatin structure is relaxed and so the genes can be transcribed.

The components that constitute epigenetics are still being collected, and when all the parts are known, a clearer picture will surely unfold. Nonetheless, great discoveries have been made in this last decade and Table 3 lists the most important and researched epigenetic mechanisms.

Table 3: Epigenetic processes

DNA methylation

Post-translational modifications of histones (histone code)

RNA interference

Noncoding RNAs (guide parts of the genome into more compacted chromatin states).

An epigenetic process can be defined as one whereby a change in phenotype is heritable but does not involve DNA mutation. Often the change in phenotype is an 'on' or 'off' effect and not a stepwise response.

When compared to genetics, epigenetics is a more malleable layer for information to be passed down; the DNA code is fixed for life, but the epigenome is flexible. This flexibility is due to the fact that the epigenetic tags can be modified in response to signals coming from the outside environment. Indeed, the type of diet we eat, stress and other signals has been found to modify the epigenome which in turn modifies our 'genomic landscape'. This could explain, for example, why some diseases affect only one in a pair of identical twins, despite the fact that they have the same genome. The epigenome malleability may also explain the multifactorial aspects of certain diseases like ischemic heart disease, obesity or diabetes mellitus. In addition, the finding of the epigenome is having repercussions on evolutionary thinking since signals from the outside world could work through the epigenome to change a cell's gene expression6, and so can adapt an organism to a changing environment.

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The fact that the epigenome provides an extra layer to deliver heritable information coded on the DNA, might have been a fundamental necessity for the rise of multicellular organisms. A multicellular organism usually starts from a fertilized egg. This has a single genome. But during its development the epigenome orchestrates this single genome via a multitude of distinct 'epigenetic programs' to form the different types of differentiated cells of the multicellular organisms (200 types in humans). This programmed variation constitutes what has been called the 'epigenetic code' and it extends the information potential of the genetic code7. Waddington described the 'variations in phenotype that occur from cell to cell during the development in a multicellular organism as the 'epigenetic landscape'8. All cells, starting from stem cells and ending to fully differentiated cells, have identical DNA sequences but they differ in the 'profile of genes' that they actually express and this expression of genes is dictated by the epigenome.

Many enzyme families are being discovered that modify the chromatin template (see below) into a transcriptionally permissive or not-permissive configuration. And epigenetics, on a molecular basis, is now being defined as 'the sum of the alterations to the chromatin template that collectively establish and propagate different patterns of gene expression (transcription) and silencing from the same genome'2. And so, while genetics is concerned with heritable information coded in gene sequences, epigenetics deals with the inheritance of information based on gene expression levels as orchestrated by the epigenome.

Thomas Jenuwein compares the genome of eukaryotes to a "library containing instructions for living organisms to develop, where books represent chromosomes". He says that all the letters in the books have been deciphered with the various genome projects done, including that of humans. He is of the opinion that epigenetics holds the promise of "producing an index that will order the chapters and books of the genetic library."

The Main Epigenetic Mechanisms

DNA methylation and histone modification are the main epigenetic modifications in


Figure 2: DNA methylation and Histone modification are the two main components of the epigenetic code (Dr Mark Hill, Molecular Development - Epigenetics (2010).

DNA Methylation

Currently, the main and widely studied epigenetic modification in humans is the cytosine methylation of DNA. A methyl donor molecule called S-adenosylmethionine donates a methyl group which is covalently added to the carbon-5 position of cytosine within the CpG dinucleotide. This reaction, which occurs after DNA synthesis, is enzyme mediated and is performed by a family of enzymes called DNA methyltransferases (DNMTs).

Research is showing that DNA methylation can lead to a status of gene silencing which can be inherited. Also genes which have promoters that are heavily methylated cannot be transcribed and are thus effectively silenced10,11. Table 4 shows medical conditions where epigenetic aberrations, also called epimutations, involving DNA methylation have been found.

Table 4: Some medical conditions where aberrant DNA methylation is involved

Medical Condition

Some comments

Rett syndrome

Mutations in the methyl-binding protein MeCP


Severe degrees of DNA hypomethylation

Fragile X mental retardation-1 (FMR)

Aberrant DNA methylation of the fragile X mental retardation-1 (FMR) gene


Protective cardiovascular genes are aberrantly DNA hypermethylated.

ICF (immunodeficiency, centromere instability, and facial anomalies)

Mutations in a major DNA methyltransferase (DNMT3b)


Many cancer cells feature hypermethylation of CpG islands at tumour suppressor genes

Histone Modification

Histone proteins that form the core of each nucleosome have tails that stick out. These histone tails have amino acids, like lysine and arginine, which can be chemically modified. These chemical modifications of these amino acids on the histone tails affect how the histone proteins interact with DNA, modifying the chromatin template structure and thus act as an epigenetic mechanism.

Figure 3: Eight histone proteins form the core of nucleosomes. Chemical tags on histone tails affect the interaction with DNA. (Bio1151 notes http://bio1151.nicerweb.com/Locked/src/notes.html)

The histone tails can be chemically modified by various ways. Indeed, they can be acetylated, methylated, phosphorylated, poly-ADP ribosylated, ubiquitinated, and glycosylated. All these chemical modifications is called the histone code12 and it determines the interaction of histone to DNA and also the interaction of nonhistone proteins with chromatin. It is this histone code (i.e. the combination of histone modifications at a certain region of the chromatin), that determines the compactness and function of the chromatin template and hence gene expression. The histone code is not the same throughout the whole chromosome but changes occur in it, depending on the region of the chromatin, the cell type, the tissue type and the external environment of the cell.

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Histone acetylation is one of the best-studied histone modifications13. Histone acetyltransferases (HATs) catalyses this acetylation and uses acetyl-coenzyme A as a donor molecule. Histone acetylation occurs largely at lysine residues of the histone H4 and H3, which are core histones. The level of histone acetylation depends on a balance between the action of HATs and histone deacetylases (HDACs). There are four families of HDACs (Table 5).

Table 5: The four families of histone deacetylases (HDACs)

Class I

HDAC 1,2,3, and 8

Class II

HDAC 4,5,6,7,9, and 10

Class III

Sirtuins 1-7

Class IV


Another well-studied histone modification is that of histone methylation. Histone methylation is linked both to activation and repression of gene trascription13,14. Histone tails can become methylated at several lysine (Table 6) and arginine residues. Lysine can be mono-, di-, and tri-methylated, whereas arginine can only be monomethylated. Histone methylation is harnessed by a family of enzymes called histone methyltransferases (HMTs). On the other hand and to balance the effect of HMTs when needed, histone demethylases (HDMs) remove methyl groups from histone.

Table 6: The best studied histone methylations at lysine residues

Histone 3

Lysine residues: K4, -9, -27, -36, and -79

Histone 4

Lysine residue: K20

Medical Repercussions

Epigenetic aberrations or epimutations, are being found to play a role in several medical diseases (Table 7).

Table 7: Medical conditions where epimutations are found




Psychiatric disorders

Diabetes mellitus


Several hereditary disorders (e.g. disorders of genomic imprinting).


Genomic changes, such as amplifications, translocations, deletions and point mutations were the targets for researchers in cancer in recent decades. They have shown that these genomic changes are involved in the development of cancer. Moreover, researchers have also discovered and identified oncogenes and tumour-suppressor genes in tumour development. An oncogene is a gene that controls cell growth and if it undergoes a mutation or a loss of function, allows cancer to develop15. A tumour suppressor gene is a gene that normally holds back a cell from excessive proliferation, usually by coding for a product that has an anti-mitotic effect. Researchers have shown that genomic mutations (of the above type) that result in enhancing the function of oncogenes or result in making tumour-suppressor genes to lose function, could lead to cancer. But this is not the whole picture to carcinogenesis.

Currently, research is also showing that the occurrence of cancer is due not only to these genetic changes, but also to epigenetic changes, specifically to alterations of the histone code and DNA methylation, involving oncogenes and/or tumour-suppressor genes.

DNA methylation was the first epigenetic alteration to be observed in cancer cells. Many cancer cells feature hypermethylation of CpG islands at tumour suppressor genes. This hypermethylation is accountable for the formation of heterochromatin (compacted chromatin) and so for the silencing of these genes thus causing the loss of their protective anti-mitotic effect. Another finding that features in many cancers is that of global hypomethylation leading to genome instability and activation of oncogenes and transposable elements16. At first sight this might seem contradictory to the first finding mentioned above, but whilst the first is on a more regional aspect, the latter is global. It also appears that the level of DNA methylation of the genome, which is sustained by DNA methyltransferase enzymes (DNMTs) is balanced within cells; over-expression of DNMTs has been linked to cancer in humans17,18.

An aberrant pattern of histone modifications at gene promoters is also another important epigenetic path to carcinogenesis. One such histone modification is the acetylation of lysine residues that is controlled by HATs and HDACs. Commonly, the existence of acetylated lysines within histone tails is associated with less-condensed chromatin and so a gene status that is transcriptionally active (Figure 3). If these acetylated lysines are deacetylated, heterochromatin forms and there is transcriptional gene silencing.

Studies are showing that there is a direct relationship between DNA methylation and histone modification and that the two form a 'reinforcing loop' between them. Upsetting this relationship disturbs the epigenome and thus also disturbs the chromatin template organization that it chemically orchestrates.

Table 8: Various Types of Modifications in the Histone Code implicated in Some Cancers

Modification of Histone code

Type of Modification


Acetylation of histone H4


Oesophageal squamous cell carcinoma, gastric cancer, testicular cancer, and acute promyelocytic leukemia (APL).

Acetylation of histone H3 at lysine 9 and 18


Human colon primary tumours and several human colon cancer cell lines; also associated with high recurrence of prostate cancer2

Tri-Methylation of K20-H4


Various solid cancers


Progress has been made in recent years to comprehend the epimutations of cardiovascular disease (CVD) and atherosclerosis, the main underlying cause of CVD. Yet, the field is still in its early days in comparison with cancer studies.

Despite this, already studies are showing 'epigenetic signatures' in cell types that are involved in CVD. Specifically, protective cardiovascular genes are being found to be aberrantly hypermethylated and so silenced because the chromatin template is rendered dense and compacted. The discovery of such 'epigenetic signatures' are crucial for three reasons. First, it is a well known fact that environmental and nutritional factors represent an important part of the multifaceted aetiology of CVD. Second, the incidence of risk factors for atherosclerosis such as obesity and diabetes is increasing all over the world and genetics is not likely to be the culprit; rather, it must be a sign of nongenetic mechanisms of gene expression due to environmental and nutritional factors. Epigenetics is thus providing an answer to understand how these CVD risk factors act at the molecular level to change gene expression patterns. Furthermore, since epigenetic mechanisms of gene regulation show a degree of flexibility and reversibility, this is conducive to justify 'epigenomic therapies' (curative and preventive) to be developed in the future.


Epigenetic chemical modifications of chromatin structure at regional levels (including DNA methylation and histone modifications) are being proposed as to how the environment contributes to autoimmunity.

For example, epigenetic mechanisms are being implicated in the pathogenesis of human systemic lupus erythematosus (SLE)20. It is being proposed that environmentally induced epigenetic changes are involved in the disease pathogenesis in those who are genetically predisposed. Such an implication is being based upon the observation that patients with SLE show identical changes in T cell DNA methylation. Also it has been shown that SLE-inducing drugs such as procainamide and hydralazine, affect T cell DNA methylation.

Similar interactions between genetic vulnerability and environmental factors that cause failure in epigenetic homeostasis, are also being implicated in other systemic autoimmune diseases such as rheumatoid arthritis and scleroderma, as well as in organ specific autoimmunity21.

Aberrations of epigenetic mechanisms that modify immune function are also being proposed to explain the development of autoimmune conditions affecting the skin. Examples include such conditions as atopic dermatitis, psoriasis and some form of vitiligo. Here, it is being proposed that when the skin is exposed to environmental agents (such as UV radiation), the epigenetic haemostatic mechanisms are disrupted leading to disrupted gene expressions affecting the immune system.

Table 9: Examples of autoimmune disease with epigenetic signatures

Systemic lupus erythematosus (SLE)

Rheumatoid arthritis


Atopic dermatitis


Some forms of vitiligo

The role of epigenetic mechanisms in autoimmune disease is only recently starting to come into focus. By comprehending these mechanisms, their effect on cell functioning and the role and type of environmental factors involved, one would be in a better position to establish how to manage these debilitating diseases in a preventive way but also in a medical therapeutic way.

Psychiatric Disorders

In the field of psychiatry, evidence is accumulating to imply that schizophrenia and bipolar disorders may be the result of epigenetic defects rather than genetic defects22. Specifically, epimutations have been found in genes that code for neurotransmitters in certain parts of the brain. Epigenetic therapies are also being evaluated to treat such disorders. For example, valproic acid (which is a histone deacetylase (HDAC) inhibitor), increases the effectiveness of anti-psychotic medications in the treatment of schizophrenia and bipolar disorder.

Table 10: Psychiatric Disorders with epigenetic signatures


Bipolar disorders


Bisphenol A (BPA) is a constituent of epoxy resins and polycarbonate plastics. The latter are used to produce various plastic items that are used to contain consumables. Researchers have demonstrated that exposing pregnant mice (specifically, viable yellow agouti mice) to bisphenol A (BPA), reduced DNA methylation in these mice. This resulted in the birth of more mice that were condemned to become obese and to have higher incidence of diabetes and cancer (breast and prostate) as adults23. Moreover, if the diet of the mother was supplemented with folic acid or phytoestrogen genistein, both of which are methyl donors, the negative effects of BPA on the epigenome was impeded.

Such evidence is being taken to point to a relationship between the increase in plastics in our environment and the rising incidence of obesity in humans and that epigenetics might be the mechanism behind it all.

Disorders of Genomic Imprinting

Genomic imprinting is a phenomenon whereby certain genes are expressed according to their parent of origin24. Implying that the imprinted genes are either expressed only from the allele coming from the mother, or in other cases from the allele coming from the father. Epigenetic modifications, specifically, DNA methylation and histone modifications that affect the mono-allelic gene, are the cause of genomic imprinting.

Table 11: Examples of genomic imprinting syndromes with epigenetic signatures

Prader-Willi syndrome (PWS)

Angelman syndrome (AS)

Beckwith-Wiedemann syndrome


Silver-Russell syndrome

Importance Of Epigenetics In Clinical Setting

Epimutation signatures associated with cancer can be used in the future as a means for assessing (i) an individual's risk status for cancer, (ii) the early detection of cancer and (iii) the monitoring of its treatment and prognosis. One of the most promising direction towards achieving these goals is the detection of hypermethylated promoter region CpG islands. Since DNA methylation epimutations are known to occur early in carcinogenesis, such aberrations are good candidates as indicators. These goals can also become applicable to other medical diseases where epimutation signatures are found.

Epigenetic-based treatment strategies are also rational and the first generation of epigenetic-based drugs has been approved by FDA. Indeed, the use of such drugs is establishing that epigenetic modulation can be a feasible treatment option, not only for cancer, but also for the growing list of diseases where epigenetic mechanisms of gene expression underline their pathogenesis25. And since epigenetic changes are thought to be responsible for a wide range of diseases, the scope of epigenetic therapy is likely to expand26.

The four epigenetic drugs available for clinical use in the U.S. include two DNA demethylating agents, 5-azacytidine and decitabine, and two histone deacetylase (HDAC) inhibitors, vorinostat and valproic acid.

Table 12: The four epigenetic drugs approved for clinical use in the U.S.

DNMTs inhibitors



DNA methyltransferase inhibitors

act as DNA demethylating agents and so reduce the levels of DNA methylation

HDAC inhibitors


valproic acid

Histone deacetylase (HDAC) inhibitors

acetyl groups are not removed from histone tails

Decitabine and 5-azacytidine inhibit DNA methyltransferase (DNMTs) enzymes and thus reduce the overall levels of DNA methylation. Vorinostat and valproic acid block histone deacetylases (HDACs) which are enzymes that remove acetyl groups from histone tails. These epigenetic drugs have been approved mainly for the treatment of blood cancers, in particular myelodysplastic syndromes (MDS).

At present, the targets for epigenetic drugs are DNMTs and HDACs, with the latter generating the most excitement, but it is worth mentioning that since many other molecules are also involved in epigenetic mechanisms in gene expression, there are other potential targets as well.

Table 13: Classification of some epigenetic drugs, their use and developmental phase



Developmental Phase

DNMT inhibitors


Myelodysplastic syndrome

FDA approved for clinical use

Solid tumours

Phase II


Phase II


Myelodysplastic syndrome

Phase II




Urinary bladder cancer



Prostate cancer


HDAC inhibitors

Valproic acid

Bipolar disorder

In routine use

Breast and ovarian cancer



Myelodysplastic syndrome

FDA approved for clinical use





New methods and tests are being discovered to detect epigenetic signatures in normal humans and in those afflicted by diseases. When all the data from such comparative epigenomic studies is analysed, it would definitely help (i) to assess risk status for a particular disease, (ii) to detect early onset of a disease and also (iii) in monitoring of treatment and prognosis of a disease. It could also help in prevention programs since certain epigenetic changes characteristic of certain diseases are reversible.

Above all, epigenetics is showing that our lifestyle and environment can change the way our genes are expressed. Indeed, studies are showing that such epimutations might even be transgenerationally inherited, putting moral responsibilities on parents, since their lifestyle might affect the health of their children and even their grandchildren.