KAT6B overexpression rescues embryonic lethality in homozygous null KAT6A mice restoring vitality and normal lifespan

Bergamasco, MI; Yang, Y; Garnham, AL; Sheikh, BN; Smyth, GK; Voss, AK; Thomas, T

Author(s): Bergamasco, MI; Yang, Y; Garnham, AL; Sheikh, BN; Smyth, GK; Voss, AK; Thomas, T;
Details: Publication Year 2025-02-25,Volume 16,Issue #1,Page 1958
Journal Title: Nature Communications
Abstract: Closely related genes typically display common essential functions but also functional diversification, ensuring retention of both genes throughout evolution. The histone lysine acetyltransferases KAT6A (MOZ) and KAT6B (QKF/MORF), sharing identical protein domain structure, are mutually exclusive catalytic subunits of a multiprotein complex. Mutations in either KAT6A or KAT6B result in congenital intellectual disability disorders in human patients. In mice, loss of function of either gene results in distinct, severe phenotypic consequences. Here we show that, surprisingly, 4-fold overexpression of Kat6b rescues all previously described developmental defects in Kat6a mutant mice, including rescuing the absence of hematopoietic stem cells. Kat6b restores acetylation at histone H3 lysines 9 and 23 and reverses critical gene expression anomalies in Kat6a mutant mice. Our data suggest that the target gene specificity of KAT6A can be substituted by the related paralogue KAT6B, despite differences in amino acid sequence, if KAT6B is expressed at sufficiently high levels.
Publisher: Springer Nature
Keywords: Animals; *Histone Acetyltransferases/genetics/metabolism; Mice; *Longevity/genetics; Acetylation; Histones/metabolism; Humans; Homozygote; Mice, Knockout; Female; Male; *Lysine Acetyltransferases/genetics/metabolism; *Embryo Loss/genetics; Hematopoietic Stem Cells/metabolism; Mutation; Gene Expression Regulation, Developmental
Research Division(s): Genetics and Gene Regulation; Bioinformatics and Computational Biology
PubMed ID: 40000651
Publisher's Version: https://doi.org/10.1038/s41467-025-57155-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-57155-4.
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-22 09:59:54

Last Modified: 2026-01-22 10:03:26