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

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  • Maria. I. Bergamasco

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Yuqing Yang

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Alexandra L. Garnham

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Bilal N. Sheikh

    (Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich
    University of Leipzig)

  • Gordon K. Smyth

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Anne. K. Voss

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Tim Thomas

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

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.

Suggested Citation

  • Maria. I. Bergamasco & Yuqing Yang & Alexandra L. Garnham & Bilal N. Sheikh & Gordon K. Smyth & Anne. K. Voss & Tim Thomas, 2025. "KAT6B overexpression rescues embryonic lethality in homozygous null KAT6A mice restoring vitality and normal lifespan," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57155-4
    DOI: 10.1038/s41467-025-57155-4
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    1. Jonathan B. Baell & David J. Leaver & Stefan J. Hermans & Gemma L. Kelly & Margs S. Brennan & Natalie L. Downer & Nghi Nguyen & Johannes Wichmann & Helen M. McRae & Yuqing Yang & Ben Cleary & H. Rache, 2018. "Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth," Nature, Nature, vol. 560(7717), pages 253-257, August.
    2. Jeffrey T Leek & John D Storey, 2007. "Capturing Heterogeneity in Gene Expression Studies by Surrogate Variable Analysis," PLOS Genetics, Public Library of Science, vol. 3(9), pages 1-12, September.
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