G9a

G9a, officially known as EHMT2 (euchromatic histone-lysine N-methyltransferase 2) and also referred to as KMT1C, is a conserved histone methyltransferase in mammals. It primarily catalyzes the dimethylation of histone H3 on lysine 9 (H3K9me2), a repressive chromatin mark associated with transcriptional silencing and chromatin compaction. The activity of G9a is largely achieved through its interaction with EHMT1 (GLP); together, the G9a–GLP complex is a major writer of H3K9me2 in many somatic tissues.

G9a contains a C-terminal catalytic SET-domain and N-terminal regions that mediate protein interactions, including ankyrin repeats. The enzymatic activity requires S-adenosyl methionine as a methyl donor. In addition to histone substrates, G9a methylates non-histone proteins such as p53, expanding its regulatory scope to various cellular processes. The G9a–GLP complex also collaborates with other chromatin factors, including HP1 proteins, to reinforce silenced chromatin states.

Biological roles and significance include regulation of gene expression during development, maintenance of cell identity, and guidance of early differentiation. In embryonic development, proper G9a function is essential; genetic disruption in model organisms leads to developmental defects and, in some cases, lethality. In the nervous system, G9a influences neuronal maturation, synaptic plasticity, and learning and memory, with tissue-specific effects observed upon loss or reduction of activity.

Clinical and research relevance: G9a is frequently overexpressed in various cancers and has been linked to tumor progression and poor prognosis. Numerous small-molecule inhibitors (for example, BIX-01294, UNC0638, UNC0642, and A-366) have been developed to study its role by reducing H3K9me2 levels. These inhibitors are primarily research tools; as of now, there are no approved clinical G9a inhibitors.