Histone deacetylase (HDAC) is a family of enzymes that function as fundamental regulators within the complex machinery of the cell. These proteins are central players in epigenetics, controlling which genes are active or inactive without changing the underlying DNA sequence. HDACs manage the accessibility of the genetic code in the nucleus and cytoplasm, influencing processes from cell division to tissue development. Their activity maintains cellular health, and misregulation is often linked to the progression of various diseases.
The Enzymatic Mechanism of Deacetylation
The core function of a histone deacetylase is to perform deacetylation, a chemical reaction that removes an acetyl group—a small molecular tag—from a target protein. This acetyl group is typically attached to a lysine residue, a specific amino acid found in many proteins. The opposing action, acetylation, is carried out by histone acetyltransferases (HATs). HDACs function as “eraser” enzymes, stripping the acetyl group from the lysine. This action has profound effects because the acetyl group is negatively charged, and its removal restores the positive charge to the lysine residue.
The human HDAC family is categorized into four classes based on structure and co-factor requirements.
Classical HDACs (Classes I, II, and IV)
The “classical” HDACs require a zinc ion to perform their deacetylation reaction. Class I HDACs are widely expressed and found mainly in the nucleus. Class II HDACs can shuttle between the nucleus and cytoplasm and tend to be more tissue-specific. Class IV shares characteristics with both Class I and II.
Sirtuins (Class III)
Class III HDACs, known as sirtuins, are evolutionarily and mechanistically distinct. They require the co-factor Nicotinamide Adenine Dinucleotide (NAD+) to catalyze their deacetylation reaction.
How HDACs Silence Gene Expression
The primary role of histone deacetylases involves their action on histone proteins, the molecular spools around which DNA is tightly wrapped. Within the cell nucleus, DNA forms a complex called chromatin, where the DNA strand is wound around histone octamers to create nucleosomes. Histone proteins have flexible tails that protrude from the nucleosome, and the acetylation status of these tails acts as a major regulatory signal.
When HATs add acetyl groups to the positively charged lysine residues on the histone tails, the negative charge of the acetyl group neutralizes the positive charge of the lysine. This neutralization loosens the grip of the histones on the negatively charged DNA, relaxing the chromatin structure into an open, accessible state. This open state allows cellular machinery, such as transcription factors and RNA polymerase, to access the gene sequence and initiate transcription, leading to gene expression.
HDACs reverse this process by removing the acetyl group, which immediately restores the positive charge to the histone tail. This positive charge increases the electrostatic attraction between the histone and the DNA backbone, causing the chromatin structure to condense and tighten. This condensation physically seals off the gene, making the DNA sequence inaccessible for transcription. The resulting tightly packed state is known as transcriptional repression or gene silencing.
Regulatory Roles Beyond Histone Proteins
While their name highlights their action on histones, HDACs act on a vast number of non-histone proteins throughout the cell, leading them to be more accurately referred to as lysine deacetylases. By regulating the acetylation of these non-histone substrates, HDACs profoundly influence protein stability, localization, and overall function.
One significant role involves the regulation of transcription factors, proteins that bind to specific DNA sequences to control genetic information flow. For instance, the activity of the tumor suppressor protein p53, often called the “guardian of the genome,” is regulated by deacetylation catalyzed by HDAC1. This deacetylation can affect p53’s stability and ability to promote cell cycle arrest or cell death, linking HDACs directly to critical cell fate decisions.
HDACs also impact proteins involved in the cellular cytoskeleton and transport mechanisms. The enzyme HDAC6, which resides primarily in the cytoplasm, deacetylates the protein tubulin, a component of the cellular highway system known as microtubules. This modification influences the movement of materials within the cell and is also involved in the cell’s response to stress. Furthermore, HDAC6 deacetylates the chaperone protein Hsp90, affecting its ability to correctly fold and stabilize other proteins.
Therapeutic Applications of Targeting HDACs
The pervasive role of HDACs in controlling gene expression and protein function makes them highly relevant targets for therapeutic intervention. Dysregulation of HDAC activity, such as the overexpression of certain isoforms, is frequently observed in various diseases, most notably in many types of cancer. This excessive activity can lead to the inappropriate silencing of tumor suppressor genes, promoting uncontrolled cell proliferation.
Targeting the enzymatic mechanism of HDACs has led to the development of Histone Deacetylase Inhibitors (HDACi), a class of drugs designed to block this deacetylase activity. By inhibiting HDACs, these compounds promote hyperacetylation—the accumulation of acetyl groups—on both histone and non-histone proteins. In cancer cells, this action can reactivate silenced tumor suppressor genes and trigger programmed cell death, or apoptosis.
Several HDAC inhibitors, such as Vorinostat and Romidepsin, are already approved by the FDA for the treatment of specific hematological malignancies, including cutaneous T-cell lymphoma. Beyond cancer, HDAC inhibitors show promise in preclinical models for various neurological disorders, including Huntington’s disease and Alzheimer’s disease. By restoring the acetylation balance in neurons, these drugs may help reverse the transcriptional silencing of genes important for neuronal health and survival.