The histone acetyltransferase KAT6B is required for hematopoietic stem cell development and function

Maria I Bergamasco; Nishika Ranathunga; Waruni Abeysekera; Connie S N Li-Wai-Suen; Alexandra L Garnham; Simon N Willis; Helen M McRae; Yuqing Yang; Angela D'Amico; Ladina Di Rago; Stephen Wilcox; Stephen L Nutt; Warren S Alexander; Gordon K Smyth; Anne K Voss; Tim Thomas

doi:10.1016/j.stemcr.2024.02.005

The histone acetyltransferase KAT6B is required for hematopoietic stem cell development and function

Stem Cell Reports. 2024 Apr 9;19(4):469-485. doi: 10.1016/j.stemcr.2024.02.005. Epub 2024 Mar 21.

Authors

Maria I Bergamasco¹, Nishika Ranathunga¹, Waruni Abeysekera¹, Connie S N Li-Wai-Suen¹, Alexandra L Garnham¹, Simon N Willis¹, Helen M McRae¹, Yuqing Yang¹, Angela D'Amico¹, Ladina Di Rago¹, Stephen Wilcox¹, Stephen L Nutt¹, Warren S Alexander¹, Gordon K Smyth², Anne K Voss³, Tim Thomas⁴

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
² The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia.
³ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: tthomas@wehi.edu.au.
⁴ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: avoss@wehi.edu.au.

PMID: 38518784
DOI: 10.1016/j.stemcr.2024.02.005

Abstract

The histone lysine acetyltransferase KAT6B (MYST4, MORF, QKF) is the target of recurrent chromosomal translocations causing hematological malignancies with poor prognosis. Using Kat6b germline deletion and overexpression in mice, we determined the role of KAT6B in the hematopoietic system. We found that KAT6B sustained the fetal hematopoietic stem cell pool but did not affect viability or differentiation. KAT6B was essential for normal levels of histone H3 lysine 9 (H3K9) acetylation but not for a previously proposed target, H3K23. Compound heterozygosity of Kat6b and the closely related gene, Kat6a, abolished hematopoietic reconstitution after transplantation. KAT6B and KAT6A cooperatively promoted transcription of genes regulating hematopoiesis, including the Hoxa cluster, Pbx1, Meis1, Gata family, Erg, and Flt3. In conclusion, we identified the hematopoietic processes requiring Kat6b and showed that KAT6B and KAT6A synergistically promoted HSC development, function, and transcription. Our findings are pertinent to current clinical trials testing KAT6A/B inhibitors as cancer therapeutics.

Keywords: KAT6A; KAT6B; chromatin; hematopoiesis; histone acetyltransferase; stem cells; transplantation.

MeSH terms

Animals
Cell Differentiation / genetics
Hematologic Neoplasms*
Hematopoiesis*
Hematopoietic Stem Cells
Histone Acetyltransferases / genetics
Mice

Substances

Histone Acetyltransferases