The human EHMT2/G9a Gene (NC_000006.11) is located on the minus strand and spans 17929 bps of genomic region (31847536 - 31865464). The long isoform of EHMT2/G9a comprises 28 exons, whereas the short isoform consists of 27 exons and lacks the sequence corresponding to exon 10 of the long isoform.

EHMT2/G9a gene has two differentially spliced transcript variants (Brown et al., 2001). G9a transcript variant I NG36/EHMT2 (accession number NM_006709.3) also called long isoform or isoform a, has 3982 bps open reading frame. G9a transcript variant II NG36/EHMT2-SP1 (accession number NM_025256.5) also called short Isoform or isoform b, has open reading frame of 3880 bps (Brown et al., 2001).

There is no known pseudogene for EHMT2/G9a.

EHMT2/G9a isoform a (accession number NP_006700.3) is composed of 1210 amino acid residues while the shorter isoform b (accession number NP_079532.5) comprises 1176 amino acid residues (Figure 2). The G9a protein contains several evolutionarily conserved domains including, the N-terminus transcription activation domain (TAD), E-rich domain containing 24 contiguous glutamic acid residues and the cysteine (Cys) rich domain that contains 12 cysteine residues, the centrally located ankyrin (ANK) domain containing seven ankyrin repeats and the C-terminus SET domain (Milner and Campbell, 1993; Brown et al., 2001; Dillon et al., 2005). Functionally, the TAD domain of G9a has been shown to be involved in transcription activation and is sufficient to activate transcription of several nuclear receptor genes (Lee et al., 2006; Purcell et al., 2011, Bittencourt et al., 2012). The E-rich domain has been shown to be present in several proteins including the nuclear protein nucleolin, the chromosomal protein HMG1 and the centromere auto-antigen CENP-B (Milner and Campbell, 1993; Brown et al., 2001). The Cys rich domain acts as a binding site for neuron-restrictive silencing factor (NRSF) and has been shown to be involved in repression of neuronal genes in non-neuronal tissue (Roopra et al., 2004). The ANK domain, which is conserved in diverse proteins including transcription factors has been shown to be involved in protein-protein interactions (Milner and Campbell, 1993; Sedgwick and Smerdon, 1999), and binding to histone mono- and dimethylated H3 lysine 9 marks (Collins et al., 2008). The C-terminal SET domain is responsible for the methyltransferase activity of G9a (Tachibana et al., 2001; Tachibana et al., 2002) and is also required for interaction with GLP (Tachibana et al., 2005).

EHMT2/G9a RNA is present in a wide range of human tissues and cells with high levels in fetal liver, thymus, lymph node, spleen and peripheral blood leukocytes and lower level in bone marrow (Milner and Campbell, 1993; Brown et al., 2001).

EHMT2/G9a is localized in the nucleus. It is mostly associated with euchromatic regions of chromatin and absent from heterochromatin (Tachibana et al., 2002).

The histone methyltransferase G9a mono and dimethylates Lys-9 of histone H3 specifically in euchromatin (Tachibana et al., 2001; Tachibana et al., 2002). Furthermore, G9a can also mono and dimethylates Lys-27 of histone H3 and mono methylates histone H1 (Tachibana et al., 2001; Chaturvedi et al., 2009; Trojer et al 2009; Weiss et al., 2010; Wu et al., 2011). In addition, G9a methylates several non-histone proteins including p53, CDYL, WIZ, CSB, ACINUS, DNMT1, HDAC1, KLF12, MyoD, DNMT3a and MTA1 (Rathert et al., 2008; Haung et al., 2010; Chang et al., 2011; Ling at al., 2012; Nair et al., 2013) and automethylates (Chin et al., 2007; Rathert et al., 2008). G9a also plays an important role in mediating DNA methylation through its association with DNA methyltransferases (Epsztejn-Litman et al., 2008; Tachibana et al., 2008; Dong et al., 2008).
Transcriptionally, G9a can function both as a corepressor and/or a coactivator of gene expression, (Collins and Cheng, 2010; Yoichi and Tachibana, 2011; Shnakar et al., 2013; Lee et al., 2006; Chaturvedi et al., 2009; Purcell et al., 2011; Chaturvedi et al., 2012; Bittencourt et al., 2012). The corepressor function of the G9a is dependent on its enzymatic activity as well as on its interaction with other factors that are involved in gene repression (Tachibana et al., 2002; Yoichi and Tachibana, 2011; Chaturvedi et al., 2012; Shnakar et al., 2013). G9a gets targeted to specific genes by associating with various transcriptional repressors and corepressors such as, CDP/Cut, E2F6, Gfi1/zfp163, Blimp-1/PRDI-BF1, REST/NRSF, ZNF217 and PRISM/PRDM6 and several others (Tachibana et al., 2002; Ogawa et al., 2002; Gyory et al., 2004; Nashio and Walsh, 2004; Roopra et al., 2004; Daun et al., 2005; Davis et al., 2006; Nagano et al., 2008; Banck et al., 2009; Yoichi and Tachibana, 2011; Shnakar et al., 2013). The coactivator function of the G9a does not require its enzymatic activity but requires association with other transcriptional activators and/or coactivators factors including CARM1, p300, RNA polymerases or the Mediator complex (Lee et al., 2006; Chaturvedi et al., 2009; Purcell et al., 2011; Bittencourt et al., 2012; Chaturvedi et al., 2012).
Functionally, G9a has been shown to play important roles in regulating the expression of genes involved in various developmental and differentiation processes. G9a is indispensible for early embryonic development (Tachibana et al., 2002; Yoichi and Tachibana, 2011). The G9a knockout embryonic stem cells (ESCs) show severe defects in differentiation, suggesting that G9a positively regulates ESCs differentiation (Tachibana et al., 2002; Feldman et al., 2006; Kubicek et al., 2007; Shi et al., 2008). Similarly, G9a is required for proper differentiation, survival and lineage commitment of adult or somatic stem cells i.e hematopoietic progenitor stem cells, retinal progenitor cells (Chen et al., 2012; Katoh et al., 1212). Genome wide studies have revealed the presence of G9a mediated large H3K9 dimethylation (H3K9me2) chromatin blocks (LOCKS) on large chromatin region in the genome (Wen et al., 2009; Chen et al., 2012). These G9a mediated LOCKS are necessary for proper differentiation as the loss of LOCKs inhibits or delays differentiation and lineage commitment of both embryonic and adult stem cells (Wen et al., 2009; Chen et al., 2012). In contrast to its positive regulatory role in maintaining differentiation, G9a has been shown to negatively regulate differentiation by repressing differentiation specific genes in myogenesis and adipogenesis (Shankar et al., 2013; Ling et al., 2012a; Ling et al., 2012b; Wang and Abete-Shen, 2011; Wang et al., 2013).
Furthermore, G9a has been shown to regulate gene expression in multiple other biological processes including, genomic imprinting (Nagano et al., 2008; Wagschal et al., 2008), germ cells development (Tachibana et al., 2007), erythropoiesis (Chaturvedi et al., 2009; Chaturvedi et al., 2012), T and B cell mediated immune response (Thomas et al., 2008; Lehnertz et al., 2010) and nuclear receptor mediated gene expression (Lee et al., 2006; Purcell et al., 2011; Bittencourt et al., 2012). In the brain, G9a is required for proper expression of genes involved in lineage specific expression (Roopra et al., 2004, Schaefer et al., 2009), memory consolidation (Gupta et al., 2012), and cocaine induced neuronal responses and behavioural plasticity (Maze et al., 2010). G9a has been also shown to plays critical role in cell proliferation (Yang et al., 2012), senescence (Takahashi et al., 2012), DNA replication (Esteva et al., 2006; Yu et al., 2012), and in the establishment of proviral gene silencing (Leung et al., 2011).

EHMT2/G9a homologues have been found in various species like chimpanzee (99.7 % homology), cow (98.1% homology), rat (95.97% homology), C. elegans (25 % homology) and mouse (95.5% homology).

No mutations have been reported so far.

No mutations have been reported so far.