Histone deacetylases (, HDAC) are a class of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s that remove
acetyl group
In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
s (O=C-CH
3) from an ε-N-acetyl
lysine amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
on a
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
, allowing the histones to wrap the DNA more tightly.
This is important because
DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of
histone acetyltransferase
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.
HDAC super family
Together with the
acetylpolyamine amidohydrolases and the
acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.
Classes of HDACs in higher eukaryotes
HDACs, are classified in four classes depending on sequence homology to the yeast original enzymes and domain organization:
HDAC (except class III) contain zinc and are known as Zn
2+-dependent histone deacetylases.
They feature a classical arginase fold and are structurally and mechanistically distinct from
sirtuins (class III), which fold into a
Rossmann architecture and are
NAD+ dependent.
Subtypes
HDAC proteins are grouped into four classes (see above) based on function and DNA sequence similarity. Class I, II and IV are considered "classical" HDACs whose activities are inhibited by
trichostatin A (TSA) and have a zinc dependent active site, whereas Class III enzymes are a family of NAD
+-dependent proteins known as
sirtuins and are not affected by TSA. Homologues to these three groups are found in yeast having the names: reduced potassium dependency 3 (Rpd3), which corresponds to Class I; histone deacetylase 1 (hda1), corresponding to Class II; and silent information regulator 2 (
Sir2), corresponding to Class III. Class IV contains just one isoform (HDAC11), which is not highly homologous with either Rpd3 or hda1 yeast enzymes, and therefore HDAC11 is assigned to its own class. The Class III enzymes are considered a separate type of enzyme and have a different mechanism of action; these enzymes are NAD
+-dependent, whereas HDACs in other classes require Zn
2+ as a cofactor.
Evolution
HDACs are conserved across evolution, showing orthologs in all eukaryotes and even in
Archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...
. All upper eukaryotes, including vertebrates, plants and arthropods, possess at least one HDAC per class, while most vertebrates carry the 11 canonical HDACs, with the exception of bone fish, which lack HDAC2 but appears to have an extra copy of HDAC11, dubbed HDAC12. Plants carry additional HDACs compared to animals, putatively to carry out the more complex transcriptional regulation required by these sessile organisms. HDACs appear to be deriving from an ancestral acetyl-binding domain, as HDAC homologs have been found in bacteria in the form of Acetoin utilization proteins (AcuC) proteins.
Subcellular distribution
Within the Class I HDACs, HDAC 1, 2, and 3 are found primarily in the nucleus, whereas HDAC8 is found in both the nucleus and the cytoplasm, and is also membrane-associated. Class II HDACs (HDAC4, 5, 6, 7 9, and 10) are able to shuttle in and out of the nucleus, depending on different signals.
HDAC6 is a cytoplasmic, microtubule-associated enzyme. HDAC6 deacetylates
tubulin,
Hsp90, and
cortactin, and forms complexes with other partner proteins, and is, therefore, involved in a variety of biological processes.
Function
Histone modification
Histone tails are normally positively charged due to
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
groups present on their
lysine and
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged
phosphate groups on the DNA backbone.
Acetylation, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
s and decreases the ability of the histones to bind to DNA. This decreased binding allows
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...
expansion, permitting genetic
transcription to take place. Histone deacetylases remove those acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. The increased DNA binding condenses DNA structure, preventing transcription.
Histone deacetylase is involved in a series of pathways within the living system. According to the ''Kyoto Encyclopedia of Genes and Genomes'' (
KEGG), these are:
* Environmental information processing;
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
;
notch signaling pathway
The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transme ...
br>
PATH:ko04330* Cellular processes; cell growth and death;
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
br>
PATH:ko04110* Human diseases; cancers;
chronic myeloid leukemiabr>
PATH:ko05220
Histone acetylation plays an important role in the regulation of gene expression. Hyperacetylated chromatin is transcriptionally active, and hypoacetylated chromatin is silent. A study on mice found that a specific subset of mouse genes (7%) was deregulated in the absence of HDAC1.
Their study also found a regulatory
crosstalk between
HDAC1 and
HDAC2 and suggest a novel function for HDAC1 as a transcriptional coactivator. HDAC1 expression was found to be increased in the prefrontal cortex of schizophrenia subjects,
negatively correlating with the expression of
GAD67
Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) and carbon dioxide (). GAD uses pyridoxal-phosphate (PLP) as a cofactor. The reaction p ...
mRNA.
Histone modification in neurons
Neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s are electrically excitable cells within the
nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
and are organized together in
circuits.
In
hippocampal neurons in culture, when spontaneous electrical activity occurred it was sufficient to cause
nuclear export
A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite ...
of the histone deacetylase HDAC4. Another histone deacetylase, HDAC5, was translocated to the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
after stimulation of calcium flux through synaptic
NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...
s.
Of 4,407
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s found in the
nuclei of rat
forebrain neurons in culture, after activation of the neurons, 2,860 changed in nuclear concentration due to nucleocytoplasmic shuttling or
sythesis or
degradation of the proteins.
After neuronal stimulation, of all proteins, HDAC4 had the largest concentration decrease, due to shuttling out of the nucleus.
A decrease in a HDAC would cause greater presence of
acetylation on histone tails. Histone acetylation is associated with active transcription of genes,
(see top figure in this section) and decrease in a histone deacetylase would have
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
effects by likely maintaining or increasing gene
transcriptions. The large decrease in HDAC4 after neuron activation may have a similarly large effect on neuronal function.
Non-histone effects
It is a mistake to regard HDACs solely in the context of regulating gene transcription by modifying histones and chromatin structure, although that appears to be the predominant function. The function, activity, and stability of proteins can be controlled by
post-translational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribo ...
s. Protein
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of
protein kinases or dephosphorylated by the action of
phosphatases
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. P ...
. The
acetylation of lysine residues is emerging as an analogous mechanism, in which non-histone proteins are acted on by acetylases and deacetylases.
It is in this context that HDACs are being found to interact with a variety of non-histone proteins—some of these are
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s and
co-regulators, some are not. Note the following four examples:
*
HDAC6 is associated with
aggresomes. Misfolded protein aggregates are tagged by
ubiquitination and removed from the cytoplasm by
dynein motors via the microtubule network to an organelle termed the aggresome. HDAC 6 binds polyubiquitinated misfolded proteins and links to dynein motors, thereby allowing the misfolded protein cargo to be physically transported to chaperones and proteasomes for subsequent destruction.
HDAC6 is important regulator of HSP90 function and its inhibitor proposed to treat metabolic disorders.
*
PTEN is an important phosphatase involved in cell signaling via
phosphoinositols and the
AKT/
PI3 kinase pathway. PTEN is subject to complex regulatory control via phosphorylation, ubiquitination, oxidation and acetylation. Acetylation of PTEN by the histone acetyltransferase p300/CBP-associated factor (
PCAF
P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53.
Structure
Several domains of PCAF can act independently or in unison to enable its funct ...
) can repress its activity; on the converse, deacetylation of PTEN by
SIRT1 deacetylase and, by
HDAC1, can stimulate its activity.
* APE1/Ref-1 (
APEX1
DNA-(apurinic or apyrimidinic site) lyase is an enzyme that in humans is encoded by the ''APEX1'' gene.
Apurinic/apyrimidinic (AP) sites (also called "abasic sites") occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging age ...
) is a multifunctional protein possessing both DNA repair activity (on abasic and single-strand break sites) and transcriptional regulatory activity associated with
oxidative stress. APE1/Ref-1 is acetylated by PCAF; on the converse, it is stably associated with and deacetylated by Class I HDACs. The acetylation state of APE1/Ref-1 does not appear to affect its
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
activity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the
parathyroid hormone gene.
*
NF-κB is a key transcription factor and effector molecule involved in responses to cell stress, consisting of a p50/p65 heterodimer. The p65 subunit is controlled by acetylation via PCAF and by deacetylation via
HDAC3
Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice.
Function
Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...
and HDAC6.
These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.
Neurodegenerative diseases
Inherited mutations in the gene encoding
FUS, an
RNA/
DNA binding protein, are causally linked to
amyotrophic lateral sclerosis (ALS).
FUS has a pivotal role in the
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
response involving its direct interaction with histone deacetylase 1 (HDAC1). ALS mutant FUS proteins are defective in the DNA damage response and in
recombinational DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
, and also show reduced interaction with HDAC1.
Ataxia-telangiectasia is due to mutation in the
''Atm'' gene. Wild-type ''Atm'' encodes a protein kinase employed in
chromatin remodeling
Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...
and in
epigenetic alterations that are required for
repairing DNA double-strand breaks.
''Atm'' mutation causes
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s to accumulate nuclear histone deacetylase 4 (HDAC4) resulting in increased histone deacetylation and altered neuronal gene expression that likely contributes to the
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophi ...
characteristic of ataxia-telangiectasia.
HDAC inhibitors
Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, for example,
valproic acid. In more recent times, HDIs are being studied as a mitigator or treatment for
neurodegenerative diseases
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophi ...
.
Also in recent years, there has been an effort to develop HDIs for cancer therapy.
Vorinostat (SAHA) was
FDA approved in 2006 for the treatment of cutaneous manifestations in patients with
cutaneous T cell lymphoma (CTCL) that have failed previous treatments. A second HDI, Istodax (
romidepsin), was approved in 2009 for patients with CTCL. The exact mechanisms by which the compounds may work are unclear, but
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
pathways are proposed.
In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons. HDIs are currently being investigated as chemosensitizers for cytotoxic chemotherapy or radiation therapy, or in association with DNA methylation inhibitors based on in vitro synergy.
Isoform selective HDIs which can aid in elucidating role of individual HDAC isoforms have been developed.
HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and, therefore, increase or repress their activity. For the four examples given above (see ''Function'') on HDACs acting on non-histone proteins, in each of those instances the HDAC inhibitor
Trichostatin A (TSA) blocks the effect. HDIs have been shown to alter the activity of many transcription factors, including
ACTR,
cMyb, E2F1,
EKLF,
FEN 1, GATA,
HNF-4, HSP90,
Ku70, NFκB,
PCNA, p53,
RB, Runx, SF1 Sp3, STAT,
TFIIE,
TCF, YY1.
The
ketone body β-hydroxybutyrate has been shown in mice to increase
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. T ...
of FOXO3a by histone deacetylase inhibition.
Histone deacetylase inhibitors may modulate the latency of some viruses, resulting in reactivation. This has been shown to occur, for instance, with a latent ''
human herpesvirus-6'' infection.
Histone deacetylase inhibitors have shown activity against certain ''Plasmodium'' species and stages which may indicate they have potential in malaria treatment. It has been shown that HDIs accumulate acetylated histone H3K9/H3K14, a downstream target of class I HDACs.
See also
*
Histone acetyltransferase (HAT)
*
Histone deacetylase inhibitor
*
Histone methyltransferase (HMT)
*
Histone-modifying enzymes
*
RNA polymerase control by chromatin structure
RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic ...
References
External links
*
Animationat
Merck
{{DEFAULTSORT:Histone Deacetylase
EC 3.5.1