KDM6

KDM6 refers to the lysine demethylase 6 family of histone demethylases, which includes KDM6A (UTX) and KDM6B (JMJD3). They are JmjC domain-containing dioxygenases that require Fe(II) and α-ketoglutarate to catalyze demethylation of histone H3 on lysine 27, specifically H3K27me3 and H3K27me2. By removing repressive methyl marks, KDM6 enzymes counteract Polycomb-mediated gene silencing and promote transcription at target loci.

In terms of function, KDM6A and KDM6B regulate gene expression programs essential for development and differentiation, including neural development, hematopoiesis, and immune responses. They can be recruited to chromatin by transcription factors and interact with other chromatin modifiers, contributing to an open chromatin state and active transcription at specific genes.

Genomic context and clinical relevance vary between the family members. KDM6A is located on the X chromosome and escapes X-inactivation; haploinsufficiency of KDM6A causes Kabuki syndrome type 1, a congenital disorder with distinctive facial features and developmental delays. KDM6B is autosomal (not on the X chromosome) and has been implicated in inflammatory gene activation and various developmental processes. Dysregulation of KDM6 enzymes has been observed in several cancers, with context-dependent alterations in activity contributing to oncogenic or tumor-suppressive outcomes.

Therapeutic and research notes: KDM6 enzymes are studied as epigenetic targets due to their opposition to Polycomb repression. Small-molecule inhibitors, such as cell-permeable derivatives of GSK-J4, suppress KDM6A/B activity and are used to investigate their roles in differentiation and disease. The therapeutic potential of targeting KDM6 remains under investigation, with outcomes dependent on tissue context and gene networks.