How Acetylation of Histone Tails Regulates Gene Expression

The genetic library in each cell contains the instructions for building and operating an entire organism. However, not all of these instructions are needed at every moment or in every cell. A skin cell, for example, does not need to access the genes that enable a liver cell to function. This requires a control system to turn specific genes “on” and “off” as needed, a process known as gene regulation. A primary aspect of this control involves the physical packaging of DNA, which determines which genes are accessible for use and which are kept silent.

The Structure of Chromatin and Histone Tails

To fit approximately two meters of DNA into a microscopic nucleus, the DNA must be extensively compacted. This is accomplished by wrapping the DNA around proteins called histones. DNA carries a negative electrical charge, while histones are positively charged, resulting in a strong electrostatic attraction that facilitates this tight winding. The basic repeating unit of this structure is the nucleosome, which consists of a segment of DNA coiled around a core of eight histone proteins. This complex of DNA and protein is known as chromatin.

Protruding from the core of each histone are flexible, unstructured ends called histone tails. These tails extend outward, making them accessible to the surrounding cellular environment. Their accessibility is significant because they can be chemically modified, which acts as signals that dictate how tightly the chromatin is packed.

The Process of Acetylation

Among the many chemical modifications on histone tails, acetylation is one of the most well-understood. This biochemical process involves the addition of an acetyl group to a specific amino acid on the histone tail, with the primary target being the lysine residue. This addition changes the chemical properties of the histone at that site.

This chemical tagging is performed by enzymes known as Histone Acetyltransferases (HATs). Functioning as “writers” of the histone code, HATs identify particular lysine residues and facilitate the transfer of an acetyl group from a donor molecule called acetyl-CoA. This action alters the histone’s structure and its interaction with DNA.

Impact on Gene Expression

The addition of an acetyl group to a lysine residue has a profound physical effect on chromatin structure. The process of acetylation neutralizes the positive charge of the lysine. This cancels the charge at that location, which weakens the electrostatic grip between the histone tail and the negatively charged DNA. This reduction in attraction causes the chromatin fiber to loosen and unwind from its tightly packed formation. This more relaxed and open state of chromatin is known as euchromatin.

This “open” euchromatic structure makes the DNA template physically accessible to the cellular machinery for gene transcription. Proteins called transcription factors and RNA polymerase can now bind to the promoter regions of genes, initiating the creation of an RNA copy. Consequently, histone acetylation is strongly associated with activating genes, turning them “on.”

Reversing the Process with Deacetylation

Gene regulation is a dynamic system that requires the ability to both activate and deactivate genes. The counterbalance to acetylation is deacetylation, the process of removing acetyl groups from histone tails. This reversal allows the cell to silence genes that are no longer required, turning them “off.”

The enzymes responsible for this task are called Histone Deacetylases (HDACs). Functioning as “erasers,” HDACs recognize acetylated lysine residues and cleave off the acetyl groups. This enzymatic action restores the positive charge to the lysine residue on the histone tail. The return of this charge re-establishes the strong electrostatic attraction between the histone and the DNA, causing the chromatin to condense back into a tight structure known as heterochromatin. In this “closed” state, the DNA is inaccessible to transcription machinery and the genes are silenced.

Role in Health and Disease

The proper balance between the activity of HATs and HDACs is necessary for normal cellular function and development. When this equilibrium is disrupted, it can lead to the inappropriate activation or silencing of genes, contributing to a wide range of diseases. Aberrant acetylation patterns are a known feature of many human pathologies, including cancer and neurodegenerative disorders.

In many forms of cancer, for example, HDAC enzymes can become overactive. This leads to the excessive removal of acetyl groups from the histones associated with tumor suppressor genes. When these genes, which control cell growth, are improperly silenced, this control is lost, which can lead to unchecked cell proliferation and tumor formation. This mechanism is also implicated in neurodegenerative conditions, where the expression of genes for neuron health may be altered by incorrect acetylation patterns. Drugs known as HDAC inhibitors are designed to block the action of HDACs, with the goal of reactivating the expression of genes that have been wrongfully silenced.