Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the EHMT1

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 ...

Structure

EHMT1 messenger RNA is

alternatively spliced Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

to produce three predicted

protein isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

s. Starting from the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

, the canonical isoform one has eight

ankyrin repeat The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and '' Drosophila'' Notch. Domains consisting of ankyrin tandem repeats mediate ...

s, a pre-SET, and a

SET domain The SET domain is a protein domain that typically has methyltransferase activity. It was originally identified as part of a larger conserved region present in the ''Drosophila'' Trithorax protein and was subsequently identified in the ''Drosophi ...

s. Isoforms two and three have missing or incomplete

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

SET domains respectively.

Function

G9A-like protein (GLP) shares an evolutionary conserved

with

G9A Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase enzyme that in humans is encoded by the ''EHMT2'' gene. G9a deposits the mono- and di-methylated states of histone H3 at lysine residue 9 ...

, responsible for

methyltransferase 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 Ro ...

activity. The SET domain primarily functions to establish and maintain H3K9 mono and di-methylation, a marker of faculative heterochromatin. When transiently over expressed, G9A and GLP form homo- and heterodimers via their SET domain. However, endogenously both enzymes function exclusively as a heteromeric complex. Although G9A and GLP can exert their methyltransferase activities independently ''in vitro'', if either G9a or Glp are knocked out ''in vivo'', global levels 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 ...

are severely reduced and are equivalent to H3K9me2 levels in G9a and Glp double knockout mice. Therefore, it is thought that G9A cannot compensate for the loss of GLP methyltransferase activity ''in vivo'', and vice versa. Another important functional domain, which G9A and GLP both share, is a region containing ankryin repeats, which is involved in protein-protein interactions. The ankyrin repeat domain also contains H3K9me1 and H3K9me2 binding sites. Therefore, the G9A/GLP complex can both methylate histone tails and bind to mono- and di-methylated H3K9 to recruit molecules, such as

DNA methyltransferase In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl ...

s, to the chromatin. H3K9me2 is a reversible modification and can be removed by a wide range of histone lysine demethylases (KDMs) including KDM1, KDM3, KDM4 and KDM7 family members. In addition to their role as histone lysine methyltransferases (HMTs), several studies have shown that G9A/GLP are also able to methylate a wide range of non-histone proteins. However, as most of the reported methylation sites have been derived from

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...

analyses, the function of many of these modifications remain unknown. Nevertheless, increasing evidence suggests methylation of non-histone proteins may influence protein stability, protein-protein interactions and regulate cellular signalling pathways. For example, G9A/GLP can methylate a number of transcription factors to regulate their transcriptional activity, including MyoD, C/EBP, Reptin, p53, MEF2D, MEF2C and MTA1. Furthermore, G9A/GLP are able to methylate non-histone proteins to regulate complexes which recruit DNA methyltransferases to gene promoters to repress transcription via the methylation of

CpG islands The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...

. Therefore, G9A and/or GLP have wide-ranging roles in development, establishing and maintaining cell identity, cell cycle regulation, and cellular responses to environmental stimuli, which are dependent on their non-histone protein methyltransferase activity.

Clinical significance

Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome or Kleefstra syndrome-1). Dysregulation of EHMT1 has been implicated in inflammatory and cardiovascular diseases.

References

External links

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