Histone methylation

Last updated August 11, 2024

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.

Function

Histone methylation, as a mechanism for modifying chromatin structure is associated with stimulation of neural pathways known to be important for formation of long-term memories and learning.^[1] Histone methylation is crucial for almost all phases of animal embryonic development.^[2]

Animal models have shown methylation and other epigenetic regulation mechanisms to be associated with conditions of aging, neurodegenerative diseases, and intellectual disability^[1] (Rubinstein–Taybi syndrome, X-linked intellectual disability).^[3] Misregulation of H3K4, H3K27, and H4K20 are associated with cancers.^[4] This modification alters the properties of the nucleosome and affects its interactions with other proteins, particularly in regards to gene transcription processes.

Histone methylation can be associated with either transcriptional repression or activation. For example, trimethylation of histone H3 at lysine 4 (H3K4me3) is an active mark for transcription and is upregulated in hippocampus one hour after contextual fear conditioning in rats. However, dimethylation of histone H3 at lysine 9 (H3K9me2), a signal for transcriptional silencing, is increased after exposure to either the fear conditioning or a novel environment alone.^[5]
Methylation of some lysine (K) and arginine (R) residues of histones results in transcriptional activation. Examples include methylation of lysine 4 of histone 3 (H3K4me1), and arginine (R) residues on H3 and H4.
Addition of methyl groups to histones by histone methyltransferases, can either activate or further repress transcription, depending on the amino acid being methylated and the presence of other methyl or acetyl groups in the vicinity.^[6]
Most often, for histone lysine methylations, histone methyltransferases (which methylate) are characterized as "writers", whereas demethylases are characterized as "erasers".^[2]^[4]

Mechanism

The fundamental unit of chromatin, called a nucleosome, contains DNA wound around a protein octamer. This octamer consists of two copies each of four histone proteins: H2A, H2B, H3, and H4. Each one of these proteins has a tail extension, and these tails are the targets of nucleosome modification by methylation. DNA activation or inactivation is largely dependent on the specific tail residue methylated and its degree of methylation. Histones can be methylated on lysine (K) and arginine (R) residues only, but methylation is most commonly observed on lysine residues of histone tails H3 and H4.^[7] The tail end furthest from the nucleosome core is the N-terminal (residues are numbered starting at this end). Common sites of methylation associated with gene activation include H3K4, H3K48, and H3K79. Common sites for gene inactivation include H3K9 and H3K27.^[8] Studies of these sites have found that methylation of histone tails at different residues serve as markers for the recruitment of various proteins or protein complexes that serve to regulate chromatin activation or inactivation.

Lysine and arginine residues both contain amino groups, which confer basic and hydrophobic characteristics. Lysine is able to be mono-, di-, or trimethylated with a methyl group replacing each hydrogen of its NH3+ group. With a free NH2 and NH2+ group, arginine is able to be mono- or dimethylated. This dimethylation can occur asymmetrically on the NH2 group or symmetrically with one methylation on each group.^[9] Each addition of a methyl group on each residue requires a specific set of protein enzymes with various substrates and cofactors. Generally, methylation of an arginine residue requires a complex including protein arginine methyltransferase (PRMT) while lysine requires a specific histone methyltransferase (HMT), usually containing an evolutionarily conserved SET domain.^[10]

Different degrees of residue methylation can confer different functions, as exemplified in the methylation of the commonly studied H4K20 residue. Monomethylated H4K20 (H4K20me1) is involved in the compaction of chromatin and therefore transcriptional repression. However, H4K20me2 is vital in the repair of damaged DNA. When dimethylated, the residue provides a platform for the binding of protein 53BP1 involved in the repair of double-stranded DNA breaks by non-homologous end joining. H4K20me3 is observed to be concentrated in heterochromatin and reductions in this trimethylation are observed in cancer progression. Therefore, H4K20me3 serves an additional role in chromatin repression.^[10] Repair of DNA double-stranded breaks in chromatin also occurs by homologous recombination and also involves histone methylation (H3K9me3) to facilitate access of the repair enzymes to the sites of damage.^[11]

Histone methyltransferase

The genome is tightly condensed into chromatin, which needs to be loosened for transcription to occur. In order to halt the transcription of a gene the DNA must be wound tighter. This can be done by modifying histones at certain sites by methylation. Histone methyltransferases are enzymes which transfer methyl groups from S-Adenosyl methionine (SAM) onto the lysine or arginine residues of the H3 and H4 histones. There are instances of the core globular domains of histones being methylated as well.

The histone methyltransferases are specific to either lysine or arginine. The lysine-specific transferases are further broken down into whether or not they have a SET domain or a non-SET domain. These domains specify exactly how the enzyme catalyzes the transfer of the methyl from SAM to the transfer protein and further to the histone residue.^[12] The methyltransferases can add 1-3 methyls on the target residues.

These methyls that are added to the histones act to regulate transcription by blocking or encouraging DNA access to transcription factors. In this way the integrity of the genome and epigenetic inheritance of genes are under the control of the actions of histone methyltransferases. Histone methylation is key in distinguishing the integrity of the genome and the genes that are expressed by cells, thus giving the cells their identities.

Methylated histones can either repress or activate transcription.^[12] For example, while H3K4me2, H3K4me3, and H3K79me3 are generally associated with transcriptional activity, whereas H3K9me2, H3K9me3, H3K27me2, H3K27me3, and H4K20me3 are associated with transcriptional repression.^[13]

Epigenetics

Modifications made on the histone have an effect on the genes that are expressed in a cell and this is the case when methyls are added to the histone residues by the histone methyltransferases.^[14] Histone methylation plays an important role on the assembly of the heterochromatin mechanism and the maintenance of gene boundaries between genes that are transcribed and those that aren’t. These changes are passed down to progeny and can be affected by the environment that the cells are subject to. Epigenetic alterations are reversible meaning that they can be targets for therapy.

The activities of histone methyltransferases are offset by the activity of histone demethylases. This allows for the switching on or off of transcription by reversing pre-existing modifications. It is necessary for the activities of both histone methyltransferases and histone demethylases to be regulated tightly. Misregulation of either can lead to gene expression that leads to increased susceptibility to disease. Many cancers arise from the inappropriate epigenetic effects of misregulated methylation.^[15] However, because these processes are at times reversible, there is interest in utilizing their activities in concert with anti-cancer therapies.^[15]

In X chromosome inactivation

In female organisms, a sperm containing an X chromosome fertilizes the egg, giving the embryo two copies of the X chromosome. Females, however, do not initially require both copies of the X chromosome as it would only double the amount of protein products transcribed as shown by the hypothesis of dosage compensation. The paternal X chromosome is quickly inactivated during the first few divisions.^[16] This inactive X chromosome (Xi) is packed into an incredibly tight form of chromatin called heterochromatin.^[17] This packing occurs due to the methylation of the different lysine residues that help form different histones. In humans X inactivation is a random process, that is mediated by the non-coding RNA XIST.^[18]

Although methylation of lysine residues occurs on many different histones, the most characteristic of Xi occurs on the ninth lysine of the third histone (H3K9). While a single methylation of this region allows for the genes bound to remain transcriptionally active,^[19] in heterochromatin this lysine residue is often methylated twice or three times, H3K9me2 or H3K9me3 respectively, to ensure that the DNA bound is inactive. More recent research has shown that H3K27me3 and H4K20me1 are also common in early embryos. Other methylation markings associated with transcriptionally active areas of DNA, H3K4me2 and H3K4me3, are missing from the Xi chromosome along with many acetylation markings. Although it was known that certain Xi histone methylation markings stayed relatively constant between species, it has recently been discovered that different organisms and even different cells within a single organism can have different markings for their X inactivation.^[20] Through histone methylation, there is genetic imprinting, so that the same X homolog stays inactivated through chromosome replications and cell divisions.

Mutations

Due to the fact that histone methylation regulates much of what genes become transcribed, even slight changes to the methylation patterns can have dire effects on the organism. Mutations that occur to increase and decrease methylation have great changes on gene regulation, while mutations to enzymes such as methyltransferase and demethyltransferase can completely alter which proteins are transcribed in a given cell. Over methylation of a chromosome can cause certain genes that are necessary for normal cell function, to become inactivated. In a certain yeast strain, Saccharomyces cerevisiae , a mutation that causes three lysine residues on the third histone, H3K4, H3K36, and H3K79, to become methylated causes a delay in the mitotic cell cycle, as many genes required for this progression are inactivated. This extreme mutation leads to the death of the organism. It has been discovered that the deletion of genes that will eventually allow for the production of histone methyltransferase allows this organism to live as its lysine residues are not methylated.^[21]

In recent years it has come to the attention of researchers that many types of cancer are caused largely due to epigenetic factors. Cancer can be caused in a variety of ways due to differential methylation of histones. Since the discovery of oncogenes as well as tumor suppressor genes it has been known that a large factor of causing and repressing cancer is within our own genome. If areas around oncogenes become unmethylated these cancer-causing genes have the potential to be transcribed at an alarming rate. Opposite of this is the methylation of tumor suppressor genes. In cases where the areas around these genes were highly methylated, the tumor suppressor gene was not active and therefore cancer was more likely to occur. These changes in methylation pattern are often due to mutations in methyltransferase and demethyltransferase.^[22] Other types of mutations in proteins such as isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) can cause the inactivation of histone demethyltransferase which in turn can lead to a variety of cancers, gliomas and leukemias, depending on in which cells the mutation occurs.^[23]

One-carbon metabolism modifies histone methylation

In one-carbon metabolism, the amino acids glycine and serine are converted via the folate and methionine cycles to nucleotide precursors and SAM. Multiple nutrients fuel one-carbon metabolism, including glucose, serine, glycine, and threonine. High levels of the methyl donor SAM influence histone methylation, which may explain how high SAM levels prevent malignant transformation.^[24]

Related Research Articles

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.

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a S_N2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

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.

<span class="mw-page-title-main">Methyllysine</span> Derivative of the amino acid residue lysine

Methyllysine is derivative of the amino acid residue lysine where the sidechain ammonium group has been methylated one or more times.

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, 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. 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 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.

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.

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

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.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R17me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 17th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R26me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 26th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R8me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 8th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

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