Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation. Histone acetylation and deacetylation are essential parts of gene regulation. These reactions are typically catalysed by enzymes with "histone acetyltransferase" (HAT) or "histone deacetylase" (HDAC) activity. Acetylation is the process where an acetyl functional group is transferred from one molecule (in this case, acetyl coenzyme A) to another. Deacetylation is simply the reverse reaction where an acetyl group is removed from a molecule. Acetylated histones, octameric proteins that organize chromatin into nucleosomes, the basic structural unit of the chromosomes and ultimately higher order structures, represent a type of epigenetic marker within chromatin. Acetylation removes the positive charge on the histones, thereby decreasing the interaction of the N termini of histones with the negatively charged phosphate groups of DNA. As a consequence, the condensed chromatin is transformed into a more relaxed structure that is associated with greater levels of gene transcription. This relaxation can be reversed by deacetylation catalyzed by HDAC activity. Relaxed, transcriptionally active DNA is referred to as euchromatin. More condensed (tightly packed) DNA is referred to as heterochromatin. Condensation can be brought about by processes including deacetylation and methylation.
Mechanism of action
Nucleosomes are portions of double-stranded DNA (dsDNA) that are wrapped around protein complexes called histone cores. These histone cores are composed of 8 subunits, two each of H2A, H2B, H3 and H4 histones. This protein complex forms a cylindrical shape that dsDNA wraps around with approximately 147 base pairs. Nucleosomes are formed as a beginning step for DNA compaction that also contributes to structural support as well as serves functional roles. These functional roles are contributed by the tails of the histone subunits. The histone tails insert themselves in the minor grooves of the DNA and extend through the double helix, which leaves them open for modifications involved in transcriptional activation. Acetylation has been closely associated with increases in transcriptional activation while deacetylation has been linked with transcriptional deactivation. These reactions occur post-translation and are reversible. The mechanism for acetylation and deacetylation takes place on the NH3+ groups of lysine amino acid residues. These residues are located on the tails of histones that make up the nucleosome of packaged dsDNA. The process is aided by factors known as histone acetyltransferases (HATs). HAT molecules facilitate the transfer of an acetyl group from a molecule of acetyl-coenzyme A (Acetyl-CoA) to the NH3+ group on lysine. When a lysine is to be deacetylated, factors known as histone deacetylases (HDACs) catalyze the removal of the acetyl group with a molecule of H2O. Acetylation has the effect of changing the overall charge of the histone tail from positive to neutral. Nucleosome formation is dependent on the positive charges of the H4 histones and the negative charge on the surface of H2A histone fold domains. Acetylation of the histone tails disrupts this association, leading to weaker binding of the nucleosomal components. By doing this, the DNA is more accessible and leads to more transcription factors being able to reach the DNA. Thus, acetylation of histones is known to increase the expression of genes through transcription activation. Deacetylation performed by HDAC molecules has the opposite effect. By deacetylating the histone tails, the DNA becomes more tightly wrapped around the histone cores, making it harder for transcription factors to bind to the DNA. This leads to decreased levels of gene expression and is known as gene silencing. Acetylated histones, the octomeric protein cores of nucleosomes, represent a type of epigenetic marker within chromatin. Studies have shown that one modification has the tendency to influence whether another modification will take place. Modifications of histones can not only cause secondary structural changes at their specific points, but can cause many structural changes in distant locations which inevitably affects function. As the chromosome is replicated, the modifications that exist on the parental chromosomes are handed down to daughter chromosomes. The modifications, as part of their function, can recruit enzymes for their particular function and can contribute to the continuation of modifications and their effects after replication has taken place. It has been shown that, even past one replication, expression of genes may still be affected many cell generations later. A study showed that, upon inhibition of HDAC enzymes by Trichostatin A, genes inserted next to centric heterochromatin showed increased expression. Many cell generations later, in the absence of the inhibitor, the increased gene expression was still expressed, showing modifications can be carried through many replication processes such as mitosis and meiosis.
Histone acetylation/deacetylation enzymes
Histone acetyltransferase (HATs) Histone Acetyltransferases, also known as HATs, are a family of enzymes that acetylate the histone tails of the nucleosome. This, and other modifications, are expressed based on the varying states of the cellular environment. Many proteins with acetylating abilities have been documented and, after a time, were categorized based on sequence similarities between them. These similarities are high among members of a family, but members from different families show very little resemblance. Some of the major families identified so far are as follows.
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