UTX and UTY Demonstrate Histone Demethylase-Independent Function in Mouse Embryonic Development

Abstract

UTX (KDM6A) and UTY are homologous X and Y chromosome members of the Histone H3 Lysine 27 (H3K27) demethylase gene family. UTX can demethylate H3K27; however, in vitro assays suggest that human UTY has lost enzymatic activity due to sequence divergence. We produced mouse mutations in both Utx and Uty. Homozygous Utx mutant female embryos are mid-gestational lethal with defects in neural tube, yolk sac, and cardiac development. We demonstrate that mouse UTY is devoid of in vivo demethylase activity, so hemizygous X ^Utx− Y ⁺ mutant male embryos should phenocopy homozygous X ^Utx− X ^Utx− females. However, X ^Utx− Y ⁺ mutant male embryos develop to term; although runted, approximately 25% survive postnatally reaching adulthood. Hemizygous X ⁺ Y ^Uty− mutant males are viable. In contrast, compound hemizygous X ^Utx− Y ^Uty− males phenocopy homozygous X ^Utx− X ^Utx− females. Therefore, despite divergence of UTX and UTY in catalyzing H3K27 demethylation, they maintain functional redundancy during embryonic development. Our data suggest that UTX and UTY are able to regulate gene activity through demethylase independent mechanisms. We conclude that UTX H3K27 demethylation is non-essential for embryonic viability.

Author Summary

Trimethylation at Lysine 27 of histone H3 (H3K27me3) establishes a repressive chromatin state in silencing an array of crucial developmental genes. Polycomb repressive complex 2 (PRC2) catalyzes this precise posttranslational modification and is required in several critical aspects of development including Hox gene repression, gastrulation, X-chromosome inactivation, mono-allelic gene expression and imprinting, stem cell maintenance, and oncogenesis. Removal of H3K27 trimethylation has been proposed to be a mechanistic switch to activate large sets of genes in differentiating cells. Mouse Utx is an X-linked H3K27 demethylase that is essential for embryonic development. We now demonstrate that Uty, the Y-chromosome homolog of Utx, has overlapping redundancy with Utx in embryonic development. Mouse UTY has a polymorphism in the JmjC demethylase domain that renders the protein incapable of H3K27 demethylation. Therefore, the overlapping function of UTX and UTY in embryonic development is due to H3K27 demethylase independent mechanism. Moreover, the presence of UTY allows UTX-deficient mouse embryos to survive until birth. Thus, UTX H3K27 demethylation is not essential for embryonic viability. These intriguing results raise new questions on how H3K27me3 repression is removed in the early embryo.