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Bergamasco, M.I.* ; Yang, Y.* ; Garnham, A.L.* ; Sheikh, B. ; Smyth, G.K.* ; Voss, A.K.* ; Thomas, T.*

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

Nat. Commun. 16:1958 (2025)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Histone Acetyltransferase Kat6b; Leukemia Zinc-finger; Hematopoietic Stem; Gene-expression; Moz; Family; Mutations; Protein; Cells; Acetylation

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 16, Issue: 1, Article Number: 1958

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)

Grants Australian Government Postgraduate Award
Victorian Government through an Operational Infrastructure Support Grant
Australian National Health and Medical Research Council