Histone deacetylase
Encyclopedia
Histone deacetylases (EC number
3.5.1) are a class of enzyme
s that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine
amino acid
on a histone
. 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
. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.
HDAC (except class III) contain zinc and are known as Zn-dependent histone deacetylases.
(TSA), whereas the third group is a family of NAD+-dependent proteins 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. The fourth group is considered an atypical category of its own, based solely on DNA sequence similarity to the others.
HDAC6 is a cytoplasmic, microtuble-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.
groups present on their lysine
and arginine
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
s and decreases the ability of the histones to bind to DNA. This decreased binding allows chromatin
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:
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 mRNA.
is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of protein kinase
s or dephosphorylated by the action of phosphatases. The acetylation
of lysine residues is emerging as an analogus 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
s and co-regulators, some are not. Note the following four examples:
These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.
. In more recent times, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases. Also in recent years, there has been an effort to develop HDIs for cancer therapy, and Vorinostat (SAHA)
has recently been approved for treatment of cutaneous T cell lymphoma (CTCL). The exact mechanisms by which the compounds may work are unclear, but epigenetic 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.
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.
EC number
The Enzyme Commission number is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze....
3.5.1) are a class of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
on a histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
. This is important because DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone acetyltransferase
Histone acetyltransferase
Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine....
. 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 identity and domain organization:| Class | Members | Catalytic sites | Subcellular localization | Tissue distribution | Substrates | Binding partners | Knockout phenotype |
|---|---|---|---|---|---|---|---|
| I | HDAC1 HDAC1 Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.-Interactions:HDAC1 has been shown to interact with RAD9A, DNMT3L, MTA1, FKBP3, CDC20, CDH1, Host cell factor C1, BUB3, Nuclear receptor co-repressor 2, IKZF1, Prohibitin, EVI1, DDX5, DNMT3A, Mothers against... |
1 | Nucleus | Ubiquitous | Androgen receptor Androgen receptor The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus... , SHP Small heterodimer partner The small heterodimer partner also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain... , p53 P53 p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer... , MyoD MyoD MyoD is a protein with a key role in regulating muscle differentiation. MyoD belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 .MyoD is one... , E2F1 E2F1 Transcription factor E2F1 is a protein that in humans is encoded by the E2F1 gene.-Interactions:E2F1 has been shown to interact with NCOA6, Retinoblastoma-like protein 1, Retinoblastoma protein, GTF2H1, SKP2, PURA, NPDC1, Sp2 transcription factor, Sp1 transcription factor, CUL1, ARID3A, TOPBP1,... , STAT3 STAT3 Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family... |
– | embryonic lethal, increased histone acetylation, increase in p21 P21 p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :... and p27 P27 P-27 are a Swiss rap group from Basel, Switzerland.They came out with the very first rap track that featured rhymes in Swiss German, on the song "Murder by Dialect" featuring Black Tiger, featured on the second Fresh Stuff compilation. The first album Overdose Funk followed the same year. Lyrics... |
| HDAC2 | 1 | Nucleus | Ubiquitous | Glucocorticoid receptor Glucocorticoid receptor The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind.... , YY1 YY1 Transcriptional repressor protein YY1 is a protein that in humans is encoded by the YY1 gene.-Interactions:YY1 has been shown to interact with Histone deacetylase 2, FKBP3, ATF6, Myc, SAP30, EP300, HDAC3, NOTCH1 and RYBP.... , BCL6 BCL6 B-cell lymphoma 6 protein is a protein that in humans is encoded by the BCL6 gene.- Function :The protein encoded by this gene is an evolutionarily conserved zinc finger transcription factor and contains an N-terminal POZ/BTB domain... , STAT3 STAT3 Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family... |
– | Cardiac defect | |
| HDAC3 HDAC3 Histone deacetylase 3 is an enzyme that in humans is encoded by the HDAC3 gene.-Interactions:HDAC3 has been shown to interact with HDAC9, HDAC7A, Retinoblastoma protein, RBBP4, Testicular receptor 2, MAP3K7IP2, Peroxisome proliferator-activated receptor delta, GTF2I, Histone deacetylase 5, RELA,... |
1 | Nucleus | Ubiquitous | SHP Small heterodimer partner The small heterodimer partner also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain... , YY1 YY1 Transcriptional repressor protein YY1 is a protein that in humans is encoded by the YY1 gene.-Interactions:YY1 has been shown to interact with Histone deacetylase 2, FKBP3, ATF6, Myc, SAP30, EP300, HDAC3, NOTCH1 and RYBP.... , GATA1 GATA1 Erythroid transcription factor also known as GATA-binding factor 1 or GATA-1 is a protein that in humans is encoded by the GATA1 gene.... , RELA RELA Transcription factor p65 is a protein that in humans is encoded by the RELA gene.-Interactions:RELA has been shown to interact with NFKBIB, ETHE1, NFKBIE, RFC1, TRIB3, CREB binding protein, Neutrophil cytosolic factor 1, Glucocorticoid receptor, MTPN, BRCA1, C-Fos, POU2F1, BTRC, TATA-binding... , STAT3 STAT3 Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family... , MEF2D MEF2D Myocyte-specific enhancer factor 2D is a protein that in humans is encoded by the MEF2D gene.-Interactions:MEF2D has been shown to interact with YWHAQ, MAPK7, EP300, Sp1 transcription factor, Myocyte-specific enhancer factor 2A, NFATC2 and CABIN1.... |
– | – | |
| HDAC8 HDAC8 Histone deacetylase 8 is an enzyme that in humans is encoded by the HDAC8 gene, and is biologically involved in skull morphogenesis and metabolic control of the ERR-alpha/PGC1-alpha transcriptional complex. -Further reading:- External links :... |
1 | Nucleus | Ubiquitous? | – | EST1B SMG5 Protein SMG5 is a protein that in humans is encoded by the SMG5 gene. This protein contains a PIN domain that appears to have mutated the residues in the active site.-Further reading:... |
– | |
| IIA | HDAC4 HDAC4 Histone deacetylase 4, also known as HDAC4, is a protein which in humans is encoded by the HDAC4 gene.- Function :Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects... |
1 | Nucleus / cytoplasm | heart, smooth muscle, brain | GCMA GCM1 Chorion-specific transcription factor GCMa is a protein that in humans is encoded by the GCM1 gene.-Further reading:... , GATA1 GATA1 Erythroid transcription factor also known as GATA-binding factor 1 or GATA-1 is a protein that in humans is encoded by the GATA1 gene.... , HP1 Heterochromatin protein 1 The family of Heterochromatin Protein 1 are highly conserved adapter proteins, which have important functions in the cell nucleus... |
RFXANK RFXANK DNA-binding protein RFXANK is a protein that in humans is encoded by the RFXANK gene.-Interactions:RFXANK has been shown to interact with RFXAP and CIITA.-Further reading:... |
Defects in chondrocyte Chondrocyte Chondrocytes are the only cells found in cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans... differentiation |
| HDAC5 | 1 | Nucleus / cytoplasm | heart, smooth muscle, brain | GCMA GCM1 Chorion-specific transcription factor GCMa is a protein that in humans is encoded by the GCM1 gene.-Further reading:... , SMAD7, HP1 Heterochromatin protein 1 The family of Heterochromatin Protein 1 are highly conserved adapter proteins, which have important functions in the cell nucleus... |
REA PHB2 Prohibitin-2 is a protein that in humans is encoded by the PHB2 gene.-Further reading:... , estrogen receptor Estrogen receptor Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled... |
Cardiac defect | |
| HDAC7 | 1 | Nucleus / cytoplasm | heart, smooth muscle, pancreas, placenta | PLAG1 PLAG1 Zinc finger protein PLAG1 is a protein that in humans is encoded by the PLAG1 gene.-Interactions:PLAG1 has been shown to interact with Karyopherin alpha 2.- External links :... , PLAG2 |
HIF1A HIF1A Hypoxia-inducible factor 1, alpha subunit , also known as HIF1A, is a protein that in humans is encoded by the HIF1A gene... , BCL6 BCL6 B-cell lymphoma 6 protein is a protein that in humans is encoded by the BCL6 gene.- Function :The protein encoded by this gene is an evolutionarily conserved zinc finger transcription factor and contains an N-terminal POZ/BTB domain... , endothelin receptor Endothelin receptor There are at least three known endothelin receptors, ETA, ETB1 and ETB2, all of which are G protein-coupled receptors whose activation result in elevation of intracellular-free calcium.-Clinical significance:... , ACTN1 ACTN1 Alpha-actinin-1 is a protein that in humans is encoded by the ACTN1 gene.-Interactions:Actinin, alpha 1 has been shown to interact with PDLIM1, Collagen, type XVII, alpha 1, CDK5R1, Zyxin, Protein kinase N1, GIPC1, SSX2IP and CDK5R2.... , ACTN4, androgen receptor Androgen receptor The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus... , Tip60 |
Maintenance of vascular integrity, increase in MMP10 MMP10 Stromelysin-2 also known as matrix metalloproteinase-10 or transin-2 is an enzyme that in humans is encoded by the MMP10 gene.- Function :... |
|
| HDAC9 HDAC9 Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.-Interactions:HDAC9 has been shown to interact with SIN3A, Nuclear receptor co-repressor 1, CBX5, HDAC3, Myocyte-specific enhancer factor 2A and SUV39H1.... |
1 | Nucleus / cytoplasm | brain, smooth muscle | – | FOXP3 FOXP3 FOXP3 is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator in the development and function of regulatory T cells.... |
Cardiac defect | |
| IIB | HDAC6 HDAC6 Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene.-Interactions:HDAC6 has been shown to interact with HDAC11 and Zinc finger and BTB domain-containing protein 16.-Further reading: -External links:... |
2 | Mostly cytoplasm | heart, liver, kidney, placenta | α-Tubulin, HSP90 Hsp90 Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress... , SHP Small heterodimer partner The small heterodimer partner also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain... , SMAD7 |
RUNX2 Runx2 Runt-related transcription factor 2 also known as core-binding factor subunit alpha-1 is a protein that in humans is encoded by the RUNX2 gene RUNX2 is a key transcription factor associated with osteoblast differentiation.... |
– |
| HDAC10 HDAC10 Histone deacetylase 10 is an enzyme that in humans is encoded by the HDAC10 gene.-Interactions:HDAC10 has been shown to interact with Histone deacetylase 2 and Nuclear receptor co-repressor 2.... |
1 | Mostly cytoplasm | liver, spleen, kidney | – | – | – | |
| III | sirtuin Sirtuin Sirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes... s in mammals (SIRT1 Sirtuin 1 Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.SIRT1 stands for sirtuin 1 , referring to the fact that its sirtuin homolog in yeast is Sir2... , SIRT2 SIRT2 NAD-dependent deacetylase sirtuin-2 is an enzyme that in humans is encoded by the SIRT2 gene.-Model organisms:The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA.-Further... , SIRT3 SIRT3 NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein... , SIRT4 SIRT4 Sirtuin 4, also known as SIRT4 is a protein which in humans is encoded by the SIRT4 gene.-Function:This gene encodes a member of the sirtuin family of proteins which are homologs of the Sir2 gene in budding yeast. Members of the sirtuin family are characterized by a sirtuin core domain and grouped... , SIRT5 SIRT5 Sirtuin 5 , also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the Sirt5 gene.... , SIRT6 SIRT6 Mono-ADP-ribosyltransferase sirtuin-6 is an enzyme that in humans is encoded by the SIRT6 gene.-External links:... , SIRT7 SIRT7 NAD-dependent deacetylase sirtuin-7 is an enzyme that in humans is encoded by the SIRT7 gene.-Further reading:... ) |
– | – | – | – | – | – |
| Sir2 Sir2 Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied... in the yeast S. cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
– | – | – | – | – | – | |
| IV | HDAC11 HDAC11 Histone deacetylase 11 is a histone deacetylase enzyme that in humans is encoded by the HDAC11 gene.It is the only Class IV HDAC.... |
2 | Nucleus / cytoplasm | brain, heart, smooth muscle, kidney | – | – | – |
HDAC (except class III) contain zinc and are known as Zn-dependent histone deacetylases.
Subtypes
HDAC proteins occur in four groups (see above) based on function and DNA sequence similarity. The first two groups are considered "classical" HDACs whose activities are inhibited by trichostatin ATrichostatin A
Trichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase families of enzymes, but not class III HDACs . TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage...
(TSA), whereas the third group is a family of NAD+-dependent proteins 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
Sir2
Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied...
); corresponding to Class III. The fourth group is considered an atypical category of its own, based solely on DNA sequence similarity to the others.
Subcellular distribution
Within the Class I HDACs, HDAC 1, 2, and 8 are found primarily in the nucleus, whereas HDAC3 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, microtuble-associated enzyme. HDAC6 deacetylates tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
, Hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
, and cortactin
Cortactin
Cortactin is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types...
, and forms complexes with other partner proteins, and is, therefore, involved in a variety of biological processes.
Histone modification
Histone tails are normally positively charged due to amineAmine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
groups present on their lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
and arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
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
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
s and decreases the ability of the histones to bind to DNA. This decreased binding allows chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
expansion, permitting genetic transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
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 transductionSignal transductionSignal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
; notch signaling pathway PATH:ko04330 - Cellular processes; cell growth and death; cell cycleCell cycleThe cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
PATH:ko04110 - Human diseases; cancers; chronic myeloid leukemia 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
Crosstalk (biology)
Biological crosstalk refers to instances in which one or more components of a signal transduction pathway affect a different pathway. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction...
between HDAC1
HDAC1
Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.-Interactions:HDAC1 has been shown to interact with RAD9A, DNMT3L, MTA1, FKBP3, CDC20, CDH1, Host cell factor C1, BUB3, Nuclear receptor co-repressor 2, IKZF1, Prohibitin, EVI1, DDX5, DNMT3A, Mothers against...
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 mRNA.
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 modifications. Protein phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s or dephosphorylated by the action of phosphatases. The acetylation
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
of lysine residues is emerging as an analogus 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
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s and co-regulators, some are not. Note the following four examples:
- HDAC6HDAC6Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene.-Interactions:HDAC6 has been shown to interact with HDAC11 and Zinc finger and BTB domain-containing protein 16.-Further reading: -External links:...
is associated with aggresomes. Misfolded protein aggregates are tagged by ubiquitinUbiquitinUbiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
ation and removed from the cytoplasm by dyneinDyneinDynein is a motor protein in cells which converts the chemical energy contained in ATP into the mechanical energy of movement. Dynein transports various cellular cargo by "walking" along cytoskeletal microtubules towards the minus-end of the microtubule, which is usually oriented towards the cell...
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. - PTENPTENPTEN may mean:* Patterson-UTI Energy, Inc., which trades on the NASDAQ stock market under the symbol 'PTEN'* Prime Time Entertainment Network* PTEN , a human tumour suppressor gene on chromosome 10...
is an important phosphatase involved in cell signaling via phosphoinositols and the AKTAKTAkt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
/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 (PCAFPCAFP300/CBP-associated factor , also known as K acetyltransferase 2B , is a human gene and trancriptional coactivator associated with p53.-Structure:...
) can repress its activity; on the converse, deacetylation of PTEN by SIRT1 deacetylase and, by HDAC1HDAC1Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.-Interactions:HDAC1 has been shown to interact with RAD9A, DNMT3L, MTA1, FKBP3, CDC20, CDH1, Host cell factor C1, BUB3, Nuclear receptor co-repressor 2, IKZF1, Prohibitin, EVI1, DDX5, DNMT3A, Mothers against...
, can stimulate its activity. - APE1/Ref-1 (APEX1APEX1DNA- lyase is an enzyme that in humans is encoded by the APEX1 gene.-Interactions:APEX1 has been shown to interact with MUTYH, Flap structure-specific endonuclease 1 and XRCC1.-Further reading:...
) is a multifunctional protein possessing both DNA repair activity (on abasic and single-strand break sites) and transcriptional regulatory activity associated with oxidative stressOxidative stressOxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. 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 repairDNA repairDNA repair refers to 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 UV light and radiation can cause DNA damage, resulting in as many as 1...
activity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the parathyroid hormoneParathyroid hormoneParathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
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 HDAC3HDAC3Histone deacetylase 3 is an enzyme that in humans is encoded by the HDAC3 gene.-Interactions:HDAC3 has been shown to interact with HDAC9, HDAC7A, Retinoblastoma protein, RBBP4, Testicular receptor 2, MAP3K7IP2, Peroxisome proliferator-activated receptor delta, GTF2I, Histone deacetylase 5, RELA,...
and HDAC6.
These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.
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 acidValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
. In more recent times, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases. Also in recent years, there has been an effort to develop HDIs for cancer therapy, and Vorinostat (SAHA)
Vorinostat
Vorinostat or suberoylanilide hydroxamic acid is a member of a larger class of compounds that inhibit histone deacetylases...
has recently been approved for treatment of cutaneous T cell lymphoma (CTCL). The exact mechanisms by which the compounds may work are unclear, but epigenetic 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.
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)
Trichostatin A
Trichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase families of enzymes, but not class III HDACs . TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage...
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.
See also
- Histone deacetylase inhibitorHistone deacetylase inhibitorHistone deacetylase inhibitors are a class of compounds that interfere with the function of histone deacetylase.HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics...
- Histone methyltransferaseHistone methyltransferaseHistone methyltransferases are enzymes, histone-lysine N-methyltransferase and histone-arginine N-methyltransferase, that catalyze the transfer of one to three methyl groups from the cofactor S-Adenosyl methionine to lysine and arginine residues of histone proteins...
- Histone-modifying enzymesHistone-Modifying EnzymesThe packaging of the eukaryotic genome into highly condensed chromatin makes it inaccessible to the factors required for gene transcription, DNA replication, recombination and repair. Eukaryotes have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin...
- RNA polymerase control by chromatin structure
External links
- Animation at MerckMerck & Co.Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...