Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation

Abstract

Histone demethylases remove transcriptional repressive marks from histones in the nucleus. KDM6A (also known as UTX) is a lysine demethylase which acts on the trimethylated lysine at position 27 in histone 3. The KDM6A gene is located on the X chromosome but escapes X inactivation even though it is not located in the pseudoautosomal region. There is a homologue of KDM6A on the Y chromosome, known as UTY. UTY was thought to have lost its demethylase activity and to represent a non-functional remnant of the ancestral KDM6A gene. However, results with knockout mice suggest that the gene is expressed and the protein performs some function within the cell. Female mice with homozygous deletion of Kdm6a do not survive, but hemizygous males are viable, attributed to the presence of the Uty gene. KDM6A is mutated in the human condition Kabuki syndrome type 2 (OMIM 300867) and in many cases of cancer. The amino acid sequence of KDM6A has been conserved across animal phyla, although it is only found on the X chromosome in eutherian mammals. In this review, we reanalyse existing data from various sources (protein sequence comparison, evolutionary genetics, transcription factor binding and gene expression analysis) to determine the function, expression and evolution of KDM6A and UTY and show that UTY has a functional role similar to KDM6A in metabolism and development.

Prenatal and perinatal history in Kabuki Syndrome

“…The relevance of histone modifications for normal development in humans is underscored through the identification of monogenic disorders of transcriptional modification (Izumi, 2016). Among these, deficiencies of KMT2D, a specific H3K4 methyltransferase, and KDM6A, a specific histone 3 lysine 27 (H3K27me3) demethylase, are associated with KS (Bogershausen et al, 2016;Gazova, Lengeling, & Summers, 2019).…”

H3K27me3 demethylase UTX regulates the differentiation of a subset of bipolar cells in the mouse retina

“…UTY has lower catalytic activity than UTX and JMJD3 due to point mutations that alter its substrate binding. However, UTY has many important noncatalytic functional roles through its intact tetratricopeptide repeat region (Gažová, Lengeling, & Summers, 2019; Walport et al, 2014).…”

Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic β-Cells

“…All of the male-enriched genes are located on the Y chromosome, whereas only two of the female-enriched genes ( Xist and Kdm6a ) are located on the X chromosome. Kdm6a , Uty , and Kdm5d all code for histone demethylases that may be involved in sex-specific epigenetic regulation of gene expression ( 65 , 66 ). Our discovery that Fmo1 , an autosome-located gene, is enriched in female β-cells is interesting, as this gene encodes a flavin-containing monooyxgenase 1, a drug-metabolizing enzyme that regulates energy balance ( 67 ).…”