Histone-modifying enzymes

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DNA is wrapped around histones to form nucleosomes. Nucleosomes are shown as "beads on a string" with the distinction between euchromatin and heterochromatin. The basic unit of chromatin organization is the nucleosome, which comprises 147 bp of DNA wrapped ar.jpg
DNA is wrapped around histones to form nucleosomes. Nucleosomes are shown as "beads on a string" with the distinction between euchromatin and heterochromatin.
The basic units of chromatin structure. Basic units of chromatin structure.svg
The basic units of chromatin structure.

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. [1] [2] To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins (H3, H4, H2A, H2B), which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. [3] [4] Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups (directly or indirectly) elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression. [4]

Contents

While there exist several distinct post-translational modifications for histones, the four most common histone modifications include acetylation, [5] methylation, [6] phosphorylation [7] and ubiquitination. [8] Histone-modifying enzymes that induce a modification (e.g., add a functional group) are dubbed writers, while enzymes that revert modifications are dubbed erasers. Furthermore, there are many uncommon histone modifications including O-GlcNAcylation, [9] sumoylation, [10] ADP-ribosylation, [11] citrullination [12] [13] [14] and proline isomerization. [15] For a detailed example of histone modifications in transcription regulation see RNA polymerase control by chromatin structure and table "Examples of histone modifications in transcriptional regulation".

Common histone modifications

The four common histone modifications and their respective writer and eraser enzymes are shown in the table below. [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

ModificationWriter(s)Eraser(s)Effect on DNA
Acetylation Histone acetyltransferases (HATs) Histone deacetylases (HDACs) Increases gene transcription
Methylation Histone methyltransferases (HMTs) Histone demethylases (KDMs)Increases or decreases gene transcription
Phosphorylation Protein kinases (PTKs) Protein phosphatases (PPs) Increases gene transcription & plays role in DNA repair and cell division
Ubiquitination Ubiquitin ligases Deubiquitinating enzymes (DUBs) Increases or decreases gene transcription & plays role in DNA repair

Acetylation

The dynamic state of histone acetylation/deacetylation regulated by HAT and HDAC enzymes; acetylation of histones alters accessibility of chromatin. Histone acetylation and deacetylation.jpg
The dynamic state of histone acetylation/deacetylation regulated by HAT and HDAC enzymes; acetylation of histones alters accessibility of chromatin.

Histone acetylation, or the addition of an acetyl group to histones, is facilitated by histone acetyltransferases (HATs) which target lysine (K) residues on the N-terminal histone tail. Histone deacetylases (HDACs) facilitate the removal of such groups. The positive charge on a histone is always neutralized upon acetylation, creating euchromatin which increases transcription and expression of the target gene. [16] Lysine residues 9, 14, 18, and 23 of core histone H3 and residues 5, 8, 12, and 16 of H4 are all targeted for acetylation. [17] [18]

Methylation

Histone methylation involves adding methyl groups to histones, primarily on lysine (K) or arginine (R) residues. The addition and removal of methyl groups is carried out by histone methyltransferases (HMTs) and histone demethylases (KDMs) respectively. Histone methylation is responsible for either activation or repression of genes, depending on the target site, and plays an important role in development and learning. [19]

Phosphorylation

A phosphoryl group is shown in blue. General structural formula of phosphoryl group.svg
A phosphoryl group is shown in blue.

Histone phosphorylation occurs when a phosphoryl group is added to a histone. Protein kinases (PTKs) catalyze the phosphorylation of histones and protein phosphatases (PPs) catalyze the dephosphorylation of histones. Much like histone acetylation, histone phosphorylation neutralizes the positive charge on histones which induces euchromatin and increases gene expression.[ citation needed ] Histone phosphorylation occurs on serine (S), threonine (T) and tyrosine (Y) amino-acid residues mainly in the N-terminal histone tails. [27]

Additionally, the phosphorylation of histones has been found to play a role in DNA repair and chromatin condensation during cell division. [22] One such example is the phosphorylation of S139 on H2AX histones, which is needed to repair double-stranded breaks in the DNA. [22]

Ubiquitination

Ubiquitination is a post-translational modification involving the addition of ubiquitin proteins onto target proteins. Histones are often ubiquitinated with one ubiquitin molecule (monoubiquitination), but can also be modified with ubiquitin chains (polyubiquitination), both of which can have variable effects on gene transcription. [23] Ubiquitin ligases add these ubiquitin proteins while deubiquitinating enzymes (DUBs) remove these groups. [24] Ubiquitination of the H2A core histone typically represses gene expression as it prevents methylation at H3K4, while H2B ubiquitination is necessary for H3K4 methylation and can lead to both gene activation or repression.[ citation needed ] Additionally, histone ubiquitination is related to genomic maintenance, as ubiquitination of histone H2AX is involved in DNA damage recognition of DNA double-strand breaks. [26]

Uncommon histone modifications

Additional infrequent histone modifications and their effects are listed in the table below. [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41]

ModificationWriter(s)Eraser(s)Effect on DNA
O-GlcNAcylation O-GlcNAc transferase (OGT) O-GlcNAcase (OGA) Increases or decreases transcription via mediation of additional histone modifications
Sumoylation E3 SUMO ligasesSUMO-specific proteasesIncreases or decreases transcription & plays role in DNA repair
ADP-ribosylation Poly-ADP ribose polymerase 1 (PARP-1)(Adp-ribosyl)hydrolases ARH1 & ARH3Decreases transcription when marking specific DNA sites for repair
Citrullination Protein arginine deiminase 4 (PAD4)No known eraserDecreases transcription via removing methylation sites
Proline isomerization Fpr4Fpr4Increases or decreases transcription via switching between H3P38 isomers (trans and cis respectively)

O-GlcNAcylation

An O-GlcNAcylated threonine residue. The GlcNAc moiety is shown in red while the modified threonine is shown in black. O-GlcNAc clear red.png
An O-GlcNAcylated threonine residue. The GlcNAc moiety is shown in red while the modified threonine is shown in black.

The presence of O-GlcNAcylation (O-GlcNAc) on serine (S) and threonine (T) histone residues is known to mediate other post-transcriptional histone modifications. The addition and removal of GlcNAc groups are performed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) respectively. While our understanding of these processes is limited, GlcNAcylation of S112 on core histone H2B has been found to promote monoubiquitination of K120. [28] Similarly, OGT associates with the HCF1 complex which interacts with BAP1 to mediate deubiquitination of H2A. OGT is also involved in the trimethylation of H3K27 and creates a co-repressor complex to promote histone deacetylation upon binding to SIN3A. [29]

Sumoylation

SUMOylation refers to the addition of Small Ubiquitin-like Modifier (SUMO) proteins onto histones. SUMOylation involves covalent attachments between SUMO proteins and lysine (K) residues on histones and is carried out in three main steps by three respective enzymes: activation via SUMO E1, conjugation via SUMO E2, and ligation via SUMO E3. In humans, SUMO E1 has been identified as the heterodimer SAE1/SAE2, SUMO E2 is known as UBE2I, and the SUMO E3 role may be a multi-protein complex played by a handful of different enzymes. [30]

SUMOylation affects the chromatin status (looseness) of the histone and influences the assembly of transcription factors on genetic promoters, leading to either transcriptional repression or activation depending on the substrate. [31] SUMOylation also plays a role in the major DNA repair pathways of base excision repair, nucleotide excision repair, non-homologous end joining and homologous recombination repair. Additionally, SUMOylation facilitates error prone translesion synthesis. [32]

ADP-ribosylation

An adenosine diphosphate ribose group. ADP ribose.svg
An adenosine diphosphate ribose group.

ADP-ribosylation (ADPr) defines the addition of one or more adenosine diphosphate ribose (ADP-ribose) groups to a protein. [33] ADPr is an important mechanism in gene regulation that affects chromatin organization, the binding of transcription factors, and mRNA processing through poly-ADP ribose polymerase (PARP) enzymes. There are multiple types of PARP proteins, but the subclass of DNA-dependent PARP proteins including PARP-1, PARP-2, and PARP-3 interact with the histone. [34] The PARP-1 enzyme is the most prominent of these three proteins in the context of gene regulation and interacts with all five histone proteins. [35]

Like PARPs 2 and 3, the catalytic activity of PARP-1 is activated by discontinuous DNA fragments, DNA fragments with single-stranded breaks. PARP-1 binds histones near the axis where DNA enters and exits the nucleosome and additionally interacts with numerous chromatin-associated proteins which allow for indirect association with chromatin. [34] Upon binding to chromatin, PARP-1 produces repressive histone marks that can alter the conformational state of histones and inhibit gene expression so that DNA repair can take place. Other avenues of transcription regulation by PARP-1 include acting as a transcription coregulator, regulation of RNA and modulation of DNA methylation via inhibiting the DNA methyltransferase Dnmt1. [34] [36]

Citrullination

The amino acid arginine (left) is converted to citrulline (right) via the process of citrullination. Citrullination.svg
The amino acid arginine (left) is converted to citrulline (right) via the process of citrullination.

Citrullination, or deimination, is the process by which the amino acid arginine (R) is converted into citrulline. Protein arginine deiminases (PADs) replace the ketimine group of arginine with a ketone group to form the citrulline. [42] PAD4 is the deaminase involved in histone modification and converts arginine to citrulline on histones H3 and H4; because arginine methylation on these histones is important for transcriptional activation, citrullination of certain residues can cause the eventual loss of methylation, leading to decreased gene transcription; [37] specific citrullination of H3R2, H3R8, H3R17, and H3R26 residues have been identified in breast cancer cells. [38] As of research conducted in 2019, this process is thought to be irreversible. [39]

Proline Isomerization

Proline trans-cis isomerization by a PPIase enzyme. Proline-cis-trans-isomerisation.svg
Proline trans-cis isomerization by a PPIase enzyme.

Isomerization involves transforming a molecule so that it adopts a different structural conformation; proline isomerization plays an integral role in the modification of histone tails. [40] Fpr4 is the prolyl isomerase enzyme (PPIase) which converts the amino acid proline (P) on histones between the cis and trans conformations. While Fpr4 has catalytic activity on a number of prolines on the N-terminal region of core histone H3 (P16, P30 and P38), it most readily binds to P38. [41]

H3P38 lies near the lysine (K) residue H3K36, and changes in P38 can affect the methylation status of K36. The two possible P38 isomers available, cis and trans, cause differential effects that are opposite of each other. The cis position induces compact histones and decreases the ability of proteins to bind to the DNA, thus preventing methylation of K36 and decreasing gene transcription. Conversely, the trans position of P38 promotes a more open histone conformation, allowing for K36 methylation and leading to an increase gene transcription. [40]

Role in research

Cancer

Alterations in the functions of histone-modifying enzymes deregulate the control of chromatin-based processes, ultimately leading to oncogenic transformation and cancer. [43] Both DNA methylation and histone modifications show patterns of distribution in cancer cells. [44] [45] These epigenetic alterations may occur at different stages of tumourigenesis and thus contribute to both the development and/or progression of cancer. [45]

Other Research

Vitamin B12 deficiency in mice has been shown to alter expression of histone modifying enzymes in the brain, leading to behavioral changes and epigenetic reprogramming. [46] Evidences also show the importance of HDACs in regulation of lipid metabolism and other metabolic pathways playing a role in the pathophysiology of metabolic disorders. [47]

See also

Related Research Articles

<span class="mw-page-title-main">Histone</span> Protein family around which DNA winds to form nucleosomes

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

<span class="mw-page-title-main">Euchromatin</span> Lightly packed form of chromatin that is enriched in genes

Euchromatin is a lightly packed form of chromatin that is enriched in genes, and is often under active transcription. Euchromatin stands in contrast to heterochromatin, which is tightly packed and less accessible for transcription. 92% of the human genome is euchromatic.

Histone H2B is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and long N-terminal and C-terminal tails, H2B is involved with the structure of the nucleosomes.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

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 by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">ADP-ribosylation</span> Addition of one or more ADP-ribose moieties to a protein.

ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.

Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome. The field is analogous to genomics and proteomics, which are the study of the genome and proteome of a cell. Epigenetic modifications are reversible modifications on a cell's DNA or histones that affect gene expression without altering the DNA sequence. Epigenomic maintenance is a continuous process and plays an important role in stability of eukaryotic genomes by taking part in crucial biological mechanisms like DNA repair. Plant flavones are said to be inhibiting epigenomic marks that cause cancers. Two of the most characterized epigenetic modifications are DNA methylation and histone modification. Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation/development and tumorigenesis. The study of epigenetics on a global level has been made possible only recently through the adaptation of genomic high-throughput assays.

H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates acetylation of the lysine residue at N-terminal position 27 of the histone H3 protein.

H2BK5ac is an epigenetic modification to the DNA packaging protein Histone H2B. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H2B protein. H2BK5ac is involved in maintaining stem cells and colon cancer.

H4K16ac is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the acetylation at the 16th lysine residue of the histone H4 protein.

H4K5ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H4 protein. H4K5 is the closest lysine residue to the N-terminal tail of histone H4. It is enriched at the transcription start site (TSS) and along gene bodies. Acetylation of histone H4K5 and H4K12ac is enriched at centromeres.

H4K8ac, representing an epigenetic modification to the DNA packaging protein histone H4, is a mark indicating the acetylation at the 8th lysine residue of the histone H4 protein. It has been implicated in the prevalence of malaria.

H4K12ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 12th lysine residue of the histone H4 protein. H4K12ac is involved in learning and memory. It is possible that restoring this modification could reduce age-related decline in memory.

H4K91ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 91st lysine residue of the histone H4 protein. No known diseases are attributed to this mark but it might be implicated in melanoma.

H3K23ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 23rd lysine residue of the histone H3 protein.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K9ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 9th lysine residue of the histone H3 protein.

H3K36ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 36th lysine residue of the histone H3 protein.

H3K56ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 56th lysine residue of the histone H3 protein.

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