KMT2D

KMT2D, also known as MLL2, is a gene that encodes a histone lysine methyltransferase belonging to the COMPASS family of epigenetic regulators. The KMT2D protein primarily methylates histone H3 on lysine 4 (H3K4), a mark associated with active transcription. In mammals, KMT2D forms part of large multi-protein complexes that include core subunits such as WDR5, RBBP5, ASH2L, and DPY30, and it contributes to methylation at promoters and enhancers, with a prominent role in enhancer activation through H3K4me1.

Structure and mechanism: KMT2D contains a SET domain near its C-terminus that carries out the methyltransferase reaction. The activity and targeting of KMT2D are governed by interactions within COMPASS-like complexes and by regulatory cofactors, enabling precise epigenetic control of gene expression during development and differentiation.

Clinical significance: KMT2D is essential for normal development. Heterozygous loss-of-function variants in KMT2D cause Kabuki syndrome type 1, a congenital disorder characterized by distinctive facial features, growth retardation, skeletal anomalies, and congenital heart defects, among other findings. The syndrome reflects haploinsufficiency of KMT2D and disrupts normal epigenetic regulation during development.

Cancer associations: Somatic mutations in KMT2D are observed in various cancers, particularly in B-cell malignancies such as follicular lymphoma and diffuse large B-cell lymphoma. Most pathogenic variants are loss-of-function, suggesting a tumor suppressor role for KMT2D in certain contexts, in which reduced H3K4 methylation alters gene expression programs.

Evolution and research: KMT2D is studied for its broader roles in epigenetic regulation, development, and disease, with ongoing research into its interactions within COMPASS-like complexes and its contributions to enhancer landscapes and transcriptional networks.