Histone Acetylation

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Introduction

The genetic material in living organisms is present in the form of DNA. This DNA does not lie within the cell in the form of threads. Rather, DNA in eukaryotes is organized into higher structures to keep it compact so that it can fit into the nucleus. 

The DNA in eukaryotes is wound around specific proteins called histone proteins to form nucleosomes. These nucleosomes along with the intervening DNA appear as beads on a string. The part DNA tightly bound to histones cannot be expressed as it is not accessible by the polymerases.

The acetylation status of histones determines how tightly they are bound to DNA. It controls the access of polymerases to the DNA and plays an important role in regulating gene expression.  

In this article, we will discuss the process of histone acetylation and deacetylation, the enzymes involved in this process, and its role in regulating the gene expression. 

Histone Proteins

It is important to understand the structure of histones before going into the detail of their acetylation. 

Histones are the highly basic proteins having abundant basic amino acids in their structure such as lysine and arginine. They are found in association with the eukaryotic DNA. The basic amino acids give these proteins a net positive charge at the physiologic pH. The phosphate groups of DNA carrying a negative charge at the physiologic pH tightly bind to these proteins via ionic interactions.

Histones proteins in eukaryotes have been divided into five major families i.e. H1, H2A, H2B, H3, and H4. The core of a nucleosome is made up of eight proteins. Two copies of each of the H2A, H2B, H3, and H4 are present in the core. These histones make dimers within the nucleosome core. Two H2A-H2B dimers and two H3-H4 dimers are present in each core. 

The H1 protein is found attached to the linker DNA, the part of DNA present between two nucleosomes.

Nucleosome formation

The octameric histone complex is formed as a result of an interaction between H4 and H2B histones. The H4 histones carry a positive charge while the H2B histones have a negative. The interaction between these two proteins causes the binding of nucleosome components and DNA is wound around it.

Histone Tails

These are the parts of histone proteins that protrude out of the core. Histone tails insert themselves into the minor groove of DNA and keep it bound to the nucleosome. These tails also attach to the linker DNA as well as other nucleosomes playing a major role in forming a highly condensed chromatin. 

Chromatin

The nucleosomes and the linker DNA are organized into a higher structure called chromatin. Depending on the accessibility of DNA, chromatin is of two types;

  • Heterochromatin, in which the DNA is highly condensed and transcriptionally inactive
  • Euchromatin, in which the DNA is less condensed and transcriptionally active

The balance between heterochromatin and euchromatin is controlled by histone acetylation and deacetylation. 

Mechanism of Acetylation

The process of acetylation involves the addition of an acetyl group to the lysine residues present in histone tails. The acetyl group is added to the amino group present in the side chain of these basic amino acids. 

The process of acetylation is facilitated by enzymes known as histone acetyltransferases. These enzymes transfer the acetyl group from acetyl CoA to the lysine residues. 

The abundant lysine residues in histone tails give them a positive charge, allowing them to tightly bind to the DNA and acidic portions of other nucleosomes. Acetylation changes the overall charge on these histone tails from positive to neutral. As a result, the interaction between DNA and histone proteins is weakened. The chromatin is decondensed and DNA becomes more accessible for transcription. 

Enzymes of Acetylation

The process of acetylation is carried out by histone acetyltransferases. These enzymes are divided into the following major families.

GNAT family

The enzymes included in this family catalyze the acetylation in the case of H3 proteins. They also acetylate H2B and H4 histones to a lesser extent.

These enzymes have 160 amino acids in their acetylation domain. They cause acetylation of lysine residues when they are a part of the nucleosome complex.

CBP family

The enzymes of this family have around 500 residues in their acetylation domain. They can cause acetylation of all the histones present in the nucleosome. 

MYST family

The enzymes in this family have around 250 amino acids in their acetylation domain. They also some other roles in different organisms in addition to histone acetylation.

Deacetylation

The process of deacetylation involves the removal of acetyl residues from the lysine residues of histone tails. This restores the positive charge on the histone tails, causing them to tightly bind to the DNA. The chromatin becomes highly condensed and DNA is not accessible for transcription. 

Enzymes of Deacetylation

The deacetylation is carried out by histone deacetylases. These enzymes have been divided into four major classes that are further divided into several subgroups. This classification of enzymes is based on their structure and conditions required for deacetylation. It is not necessary to go into the details of these classes. 

Biological Importance

The acetylation/deacetylation plays some important biological functions in eukaryotic organisms. 

Regulation of Gene Expression

Histone acetylation is a type of DNA modification that helps in regulating the gene expression in the eukaryotic cell. Recall that gene expression is the transfer of genetic information in DNA to the cytoplasm for protein synthesis. It involves copying the genetic information in the form of mRNA transcript and translation of this transcript to form proteins. 

The DNA in eukaryotes is highly condensed so that it can pack in the nucleus. The tightly packed DNA is not available for transcription by RNA polymerase. It must be first decondensed and made available for the transcription enzymes. This decondensation of DNA is done via histone acetylation. 

Histone acetylation regulates the gene expression in eukaryotes by acting as a switch between two forms of chromatin; repressive or heterochromatin and permissive or euchromatin.

Repressive Chromatin

Repressive or heterochromatin is the highly condensed form of chromatin. The DNA of this chromatin is not available for transcription. The genes present in this DNA are not expressed. The DNA, in this case, is tightly bound to the histones and is not available for reading and transcription by the different RNA polymerases. RNA polymerase can only identify and bind to the promoter region of the gene when it is present in the non-condensed form.

Permissive Chromatin

In the case of permissive chromatin, the DNA is less condensed. It is less tightly bound to the histone proteins. The spacing between the nucleosomes is greater in this type of chromatin i.e. the length of linker DNA is greater. The RNA polymerase can easily identify and bind to the promoter regions causing transcription. The genes present in this DNA are highly expressed. 

It has been found that histone acetylation acts as a switch between repressive and permissive chromatin. The highly transcribed genes have hyperacetylated histones associated with them. It has been found that transcription can occur without any hindrance in the case of chromatin having hyperacetylated nucleosomes. 

Nucleosomes have been found to halt the elongation phase of gene transcription. These histone particles in these nucleosomes can be modified via acetylation to facilitate the process of transcription. 

Gene silencing 

Just like the histone acetylation facilitates the expression of a gene, the deacetylation of histone particles can cause gene silencing. It has been found that there exist certain DNA methylase enzymes that can cause methylation of DNA at different locations. The methylated DNA then recruits the histone deacetylases enzymes. These enzymes restore the positive charges on the histone particles which in turn tightly bind to the DNA. The transcriptional machinery of the cell cannot access the tightly bound and as a result, the gene is silenced. 

The balance between histone acetylation and deacetylation regulates access to the DNA and thus, the gene expression in eukaryotes. 

Clinical Importance

Histone acetylation and deacetylation also play an important role in different diseases. Certain drugs act by changing the acetylation status of some specific genes. 

Inflammatory Diseases

Inflammatory diseases result from the excess activation and expression of some inflammatory genes such as NF-kB and AP-1. The anti-inflammatory drugs like corticosteroids perform their anti-inflammatory action by activating the histone deacetylases. This results in silencing the inflammatory genes. 

The balance between acetylation and deacetylation is important in the inflammatory diseases of the respiratory system. The patients with asthma and chronic obstructive pulmonary diseases have shown increased activity of histone acetyltransferases in the lungs.

Cancer

Cancer is uncontrolled, irreversible growth of cells. cells continue to divide without any check. A balance between the expression of oncogene and tumor suppressor genes limits the chances of cancer development in our body. 

In recent years, it has been found that histone deacetylation of certain tumor suppressor genes is involved in carcinogenesis and metastasis of certain cancers. 

Some anti-cancer drugs perform their action by changing the acetylation status of oncogenes and tumor suppressor genes. They can also limit the cancer spread by causing the deacetylation of the mutant gene, resulting in the silencing of the abnormal chromatin. 

Addiction

the recent experiments have shown that certain addictions are due to hyperacetylation of some genes, causing dependence on the addictive substance. It is especially important in the case of nicotine and cocaine addiction. 

It has been found that the administration of nicotine to the ice for 7 consecutive days resulted in hyperacetylation of certain genes in the nucleus accumbens of the brain. The increased expression of this gene stimulates the reward center of the brain and plays a role in the development of addiction. 

The same experiment was performed with cocaine and similar results were obtained. It is now understood that hyperacetylation of certain genes in the brain is the cause of addiction development. 

Cardiac Hypertrophy

An association has also been found between altered heart functions in cardiac hypertrophy and acetylation of genes. It is suggested that increased cardiac stress changes the acetylation status of certain hypertrophy responsive genes in cardiomyocytes.

Summary

The DNA in eukaryotic cells is highly condensed with histone proteins to form chromatin so that it can be kept within the small nucleus in the cells. 

Histones are highly basic proteins that form the core of nucleosomes. Eight histones are present in the core in the form of dimers. 

Histone tails protfurde from the globular part and are inserted into the DNA, keeping it tightly bound in the nucleosome. 

The acetylation of histones involves the transfer of acetyl groups from acetyl CoA to the amino gourp in the side chains of lysine residues in histone tails. the histone tails lose their positive charge, the DNA becomes free for transcription. 

This acetylation profess is catalyzed by histone acetyltransferases, that are divided into major families.

The acetyl groups can be removed by other enzymes called acetone deacetylases. The removal of acetyl groups restores the positive charges on histone tails, the DNA again becomes condensed and unavailable for transcription.

Histone acetylation controls gene expression in eukaryotes by regulating the balance between two forms of chromatin, repressive chromatin and permissive chromatin.  Repressive chromatin can be changed to permissive chromatin by histone acetylation. 

The deacetylation of histones can turn-off a gene, a process called gene silencing. 

Certain diseases involve over expression of some genes. Such diseases can be treated by drugs that alter the acetylation status. Examples of such diseases include inflammatory diseases and cancer. 

Histone acetylation has also been found to play a role in the development of addiction and the altered cardiac functions in cardiac hypertrophy. 

References

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  7. https://en.wikipedia.org/wiki/File:Nucleosome_structure.png
  8. https://en.wikipedia.org/wiki/File:Histone_acetylation_and_deacetylation.jpg
  9. https://en.wikipedia.org/wiki/NF-%CE%BAB#/media/File:NFKB_mechanism_of_action.png