Epigenetics

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Introduction

The tern ‘Epigenetics’ is used for the changes in DNA that can alter phenotype or trait without altering the nucleotide sequence present in the DNA. These are the heritable changes that can affect gene expression. Any change in gene expression will lead to a change in the phenotype of that gene or the trait being expressed. 

Epigenetic studies reveal that all the somatic cells in one species have essentially the same DNA content. However, gene expression in various types of cells shows different patterns that must be inherited. The changes in gene expression are due to epigenetics. Epigenetics involves various mechanisms that can alter gene expression at different levels of transcription and translation. 

In this article, we will study how different epigenetic mechanisms can alter gene expression. We will also study the history of epigenetics, modern advancements in this field as well as its role in various diseases.

Epigenetic Modifications

Epigenetic modifications allow different patterns of gene expression in different cell types. These modifications allow cells to express specific genes that are necessary for the existence of different cell types. These modifications can occur at any phase during the life of an organism and are passed on to the next generation. Three important epigenetic modifications are as follows. 

DNA Methylation and Demethylation 

DNA methylation involves the addition of methyl groups to DNA bases. Methyl groups can be added to two of the four bases present in DNA; adenine and cytosine. The process of methylation is carried out by enzymes called DNA methyltransferases. The methyl groups are donated by S-adenosylmethionine. 

In mammals, DNA methylation takes place at specific sequences called CpG sequences or CpG islands. Vitamin B-12 and folic acid are needed for the reactivation of S-adenosylmethionine. 

Methylation of DNA at the CpG sequences present in the promoter region leads to gene silencing. The methylated DNA is recognized by certain proteins. These proteins bind to the methylated DNA region and recruit certain chromatin remodeling complexes. These complexes stabilize the heterochromatin and thus prevent gene expression. It has been seen that transcriptionally active genes are less methylated (hypomethylated) than the transcriptionally inactive genes.

The methyl groups added to the DNA can be removed by the process of demethylation. This demethylation can take place either directly or indirectly. 

  • In the direct method, the methyl group is passively removed from methylcytosine. 
  • In the indirect method, methylcytosine is first converted to hydroxymethyl cytosine. The hydroxymethyl residue is then removed from the DNA via TET enzymes. 

Importance

DNA methylation is the most common and most stable epigenetic mark. It serves the following functions;

  • The balance between DNA methylation and demethylation determines the access to the DNA during transcription and thus controls gene expression. It one of the important means of regulation of gene expression in eukaryotes. 
  • It plays a role in gene stability. 
  • It plays an important role during mismatch repair, a type of DNA repair mechanisms. During this process, the Mut proteins differentiate the parent strand from the daughter stand based on its methylation status. The parent strand is hypermethylated while the daughter strand is hemimethylated. 

Histone Modifications

This is the second most important mechanism of epigenetic modifications. Histones are the basic proteins that present in association with the eukaryotic DNA to form nucleosomes. These nucleosomes are then arranged to form chromatin that can be highly condensed (heterochromatin) or loosely packed (euchromatin). The genes present in euchromatin are expressed while those present in heterochromatin are silenced and cannot be expressed. 

Histone modifications involve histone acetylation and deacetylation. Histone proteins are tightly bound to DNA due to the positive charges imparted to them by their basic amino acids. Histone tails are structures that emerge from the histone complex and insert into the minor groove of DNA. These tails have abundant lysine residues carrying a positive charge. The DNA tightly binds to these histone tails through the ionic interactions between the positive charge of lysine residues and negative charges on DNA phosphate groups. 

The acetylation process serves to neutralize the positive charges on histone tails. Specific histone acetyltransferase enzymes catalyze the transfer of acetyl group from acetyl-CoA to the lysine residues. The histone tails become neutral, the ionic interaction becomes weak and DNA becomes less condensed. The acetylation process changes heterochromatin into euchromatin, causing activation of the gene. 

Contrary to this, the removal of acetyl groups from the histone tails restores their positive charges, the DNA becomes tightly bound to the histones and is more tightly condensed. This process changes euchromatin to heterochromatin, resulting in gene silencing. 

in addition to histone acetylation and deacetylation, other histone modifications that play an important role in epigenetics are phosphorylation and ribosylation, etc. 

Importance

Histone modifications perform the following roles in eukaryotes. 

  • They can cause a switch between euchromatin and heterochromatin
  • They can cause gene silencing and gene activation
  • They regulate gene expression in eukaryotes by regulating the access of transcription enzymes to DNA

Mitotic Gene Bookmarking

It involves the transfer of gene expression mechanisms from the parent cell to the daughter cell during the process of mitosis. Recall that the process of transcription stops prior to mitosis. The mitotic chromatin is transcriptionally inactive and is devoid of any kind of transcription factors. 

Gene bookmarking treats the transcription process just like reading a book. The transcription process stops before the mitotic process just like closing a book while reading. Mitotic gene bookmarking acts as a molecule bookmark that allows the process of transcription to continue in the daughter cells after the process of transcription. 

This bookmarking can occur in the following ways;

  • Certain histone modifications take place before mitosis. They remain unchanged during the mitotic process and can act as a bookmark. 
  • DNA methylation can also occur before the mitotic process. The methylated DNA patterns also remain unchanged during mitosis and can serve as gene bookmarks. 

DNA methylation is more important than histone modification. It can effectively stop the transcription process during mitosis and resume it after the cell division. Different histone modifications do not show a much clear role. 

Environmental Influences

Different epigenetic modifications in the DNA of an organism can be influenced by various environmental factors such as food, stress, and environmental toxins. 

Food

Folate and vitamin B12 are the most important food components that influence epigenetic modifications. Both of these components are required to regenerate S-adenosylmethionine so that DNA methylation can continue. The defect or absence of folate or vitamin B12 can result in hypomethylation of DNA which in turn can cause several diseases. 

Stress

Recent studies have reported that stress levels can influence the extent of DNA methylation and gene expression. It has found that the gene expression in people with post-traumatic stress disorder is different as compared to healthy individuals. Similarly, maternal stress during the gestational period cause altered gene expression in the fetus and can result in several neurological and psychiatric disorders. 

Toxins

Different toxins can also influence the epigenetic modifications. The following are some examples.

  • Some bacterial toxins can dramatically change the acetylation status of histone
  • Arsenic poisoning can alter DNA methylation, histone acetylation, histone phosphorylation, and other histone modifications. It can even cause carcinogenesis.

Biological Importance

Epigenetics plays an important role in several biological processes. You have already s6tudied that different epigenetic modifications can cause gene silencing and gene activation. They can control gene expression in different cells, determining their types. 

Different animal studies have shown that DNA methylation plays an important role in fear-related memory in rats.

It has also been suggested that histone modifications and DNA methylation can influence the formation of memory and long-term memory storage in different areas of the brain. 

The study of epigenetic markers has made it possible to predict the aging of tissues in different studies. The role of DNA methylation in biological clocks has made this prediction possible. 

Clinical Importance

The scientists have tried to explain various disorders based on genetic and environmental influences for several years. However, modern developments in the field of epigenetics in the last couple of years have helped to describe some complex human disorders such as cancer, autoimmune diseases, psychiatric diseases, etc. 

DNA methylation is the most commonly used epigenetic modification by the cells. it has been linked with a couple of human diseases described below. 

Cancer

Different epigenetic modifications can affect the state of cancer. Recall that gene silencing can occur as a result of DNA hypermethylation. The tumor suppressor genes save cells from carcinogenesis. The silencing of tumor suppressor genes due to hypermethylation in the promoter region can cause tumor formation in various cells. It can also act as an early marker of carcinogenesis as in the case of the APC gene. 

Here are the examples of some cancers arising from hypermethylation and silencing of some genes. 

  • Breast cancer, due to hypermethylation of BRCA1 and other genes
  • Gastric cancer due to hypermethylation of the RUNX3 gene
  • Esophageal cancer due to hypermethylation of the APC gene
  • Colorectal cancer due to hypermethylation of the SEPT9 gene
  • Liver cancer due to hypermethylation of the CDKN2A gene

Autoimmune Disorders

Autoimmune disorders result from the absence of self-tolerance of the immune system. As a result, the immune system of a person recognizes own body cells as foreign target cells and start destroying them. 

Epigenetic modifications either in the components of the immune system or in the target cells can result in autoimmune disorders. 

The following are two examples of epigenetic modifications causing autoimmune disorders. 

  • In rheumatoid arthritis, the synovial joints have been studied to have DNA hypomethylation of histone deacetylase genes, resulting in hyperacetylation of H3 and H4 histones. 
  • DNA hypomethylation has been seen in the central nervous system of patients with multiple sclerosis. 

Neurological Disorders

Several neurological disorders can also arise due to certain epigenetic modifications. The important ones are as follows; 

  • Fragile-X syndrome
  • Huntington disease
  • Autism
  • Down syndrome
  • Bipolar disorder 
  • Dementia

These disorders can result from changes in DNA methylation or histone acetylation. These changes can occur either during the embryonic phase of life or during early childhood. The adult neurodegenerative disorders involve changes in the later years of age. Certain chromatin remodeling drugs can also play their role in the development of these disorders. 

Summary

Epigenetics involves the heritable changes in DNA that affect gene expression in cells without changing the nucleotide sequence of the genes. These alterations are responsible for the existence of different cell types even though all the somatic cells of a species contain the same amount of DNA.  They can cause gene activation as well as gene silencing. 

DNA methylation is the most widely used epigenetic modification by the cells. The methyl groups are added to the adenine or cytosine bases of DNA by methyltransferases. These methyl groups are donated by S-adenosylmethionine that requires folic acid and vitamin B12 for regeneration. 

Hypermethylated DNA is transcriptionally inactive and the genes present in it are silenced. The removal of methyl groups converts it into transcriptionally active DNA. 

Histone modifications are the second mechanism adopted by cells for epigenetic changes. The most important histone modification is histone acetylation that makes the DNA available for transcription. It acts as a switch between euchromatin and heterochromatin. Other histone modifications include ribosylation and phosphorylation, etc. 

Mitotic gene bookmarks act as molecular bookmarks that are responsible for resuming the transcription process after the cell division is completed. Again, DNA methylation acts as an important bookmark as it cannot be changed during mitosis. 

Epigenetic modifications can be influenced by environmental factors like food, stress, and toxins. 

  • Folate and Vitamin B12 are needed for DNA methylation
  • Stress can alter methylation status and gene expression
  • Toxins produced by certain bacteria as well as arsenic poisoning can badly affect the status of DNA methylation and histone acetylation

Epigenetic plays an important role in the following biological process;

  • Regulation of gene expression
  • Biological clocks and prediction of aging of tissues
  • Formation of memory
  • Storage of long-term memory
  • Formation of fear-related memory

The advancements in epigenetics have also helped in better understanding various human cancers, autoimmune diseases, and neurological disorders. 

References

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  5. https://commons.wikimedia.org/wiki/File:DNA_methylation.png
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