Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a
histone methyltransferase
Histone methyltransferases (HMT) are histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of ...
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''EHMT2''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
G9a deposits the mono- and di-methylated states of
histone H3
Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal end, N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'b ...
at
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
residue 9 (i.e.,
H3K9me1 and
H3K9me2
H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H ...
) and lysine residue 27 (
H3K27me1 and H3K27me2).
The presence of H3K9me1/2 is usually associated with
gene silencing
Gene silencing is the regulation of gene expression in a cell to prevent the expression of a certain gene. Gene silencing can occur during either Transcription (genetics), transcription or Translation (biology), translation and is often used in res ...
.
Function
A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. This gene is found near this cluster; it was mapped near the gene for C2 within a 120-kb region that included a HSP70 gene pair. These genes are all within the human major histocompatibility complex class III region. This gene was thought to be two different genes, NG36 and G9a, adjacent to each other but a recent publication shows that there is only a single gene. The protein encoded by this gene is thought to be involved in intracellular protein-protein interaction. There are three alternatively spliced transcript variants of this gene but only two are fully described.
G9a and
G9a-like protein, another histone-lysine N-methyltransferase, catalyze the synthesis of
H3K9me2
H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H ...
, which is a
repressive mark.
G9a is an important control mechanism for
epigenetic regulation within the
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for ' nucleus adjacent to the septum') is a region in the basal forebrain rostral to the preoptic area of the hypo ...
(NAcc);
reduced G9a expression in the NAcc plays a central role in mediating the development of an
addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
.
G9a opposes increases in
ΔFosB
Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (''FOSB'') gene.
The FOS gene family consists of four members: FOS, F ...
expression via
H3K9me2
H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H ...
and is suppressed by ΔFosB.
G9a exerts opposite effects to that of ΔFosB on drug-related behavior (e.g.,
self-administration
Self-administration is, in its Medicine, medical sense, the process of a subject administering a Pharmacology, pharmacological substance to themself. A clinical example of this is the subcutaneous "self-injection" of insulin by a Diabetes, diabetic ...
) and synaptic remodeling (e.g.,
dendritic arborization – the development of additional tree-like
dendritic branches and
spines) in the nucleus accumbens, and therefore opposes ΔFosB's function as well as increases in its expression.
G9a and ΔFosB share many of the same gene targets.
Figure 4: Epigenetic basis of drug regulation of gene expression
/ref> In addition to its role in the nucleus accumbens, G9a play a critical role in the development and the maintenance of neuropathic pain.dorsal root ganglia
A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dors ...
. This transcriptomic change reprograms the sensory neurons to a hyperexcitable state leading to mechanical pain hypersensitivity. [
]
Interactions
EHMT2 has been shown to interact with KIAA0515 and the prostate tissue associated homeodomain protein NKX3.1.
EHMT2 in cancer
EHMT2 is known to drive process such as self-renewal and tumorigenicity
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
, and its dysregulation can be associated with cancer. Abnormal EHMT2 expression is found both in haematological malignancies, as for example leukemia
Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
, and in solid tumors
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
, as colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...
, lung cancer
Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
, head and neck tumours.
References
Further reading
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{{PDB Gallery, geneid=10919