G9aGLP

G9a-GLP is the heterodimeric histone-lysine N-methyltransferase complex formed by G9a (EHMT2) and GLP (EHMT1). It primarily di- and mono-methylates histone H3 on lysine 9 (H3K9me2/me1), supporting transcriptional repression and chromatin compaction.

Structure and activity: G9a and GLP contain N-terminal regions that promote protein interactions and a C-terminal SET domain that carries the catalytic activity. As an obligate pair, GLP stabilizes and enhances G9a's methyltransferase function, enabling efficient H3K9 methylation.

Biological roles: The complex regulates development, differentiation, imprinting, and X-chromosome inactivation, and participates in silencing transposable elements. In the brain, it influences neuronal maturation, learning, and memory, with broader effects on gene expression programs.

Regulation and substrates: In addition to histones, G9a-GLP can methylate non-histone substrates such as p53. Locus targeting relies on transcription factors and chromatin context; activity is modulated by signaling pathways and interactions with other chromatin modifiers.

Inhibition and research tools: Small-molecule inhibitors including BIX-01294, UNC0638, and UNC0642 suppress G9a-GLP activity and are widely used to study epigenetic regulation. Pharmacokinetic properties and selectivity vary among compounds, influencing experimental design and interpretation.

Clinical relevance: Dysregulation of EHMT1 or EHMT2 is linked to neurodevelopmental disorders (notably Kleefstra syndrome from EHMT1 haploinsufficiency) and to various cancers, underscoring the complex role of G9a-GLP in development and disease.