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

The histone lysine acetyltransferase KAT6B (MYST4, MORF, QKF) is the target of recurrent chromosomal translocations causing haematological malignancies with poor prognosis. Using Kat6b germline deletion and overexpression in mice, we determined the role of KAT6B in the haematopoietic system. We found that KAT6B sustained the fetal haematopoietic 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 haematopoietic reconstitution after transplantation. KAT6B and KAT6A cooperatively promoted transcription of genes regulating haematopoiesis, including the Hoxa cluster, Pbx1, Meis1, Gata family, Erg and Flt3. In conclusion, we identified the haematopoietic 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. Overall design: Hematopoietic stem and multipotent progenitor cells - lineage marker negative, SCA1 positive, c-KIT positive (LSK) cells; were isolated by FACS from gestational day 14.5 fetal mouse livers. Mice were either C57Bl6 or FvbxBalbC background. Of those from C57Bl6, there were n=4 mice of each genotype: wild-type (WT), Kat6b-/- null (DEC/DEC), Kat6a-/+ single heterozygous (CFD/+), and Kat6a-/+ Kat6b-/+ double heterozygous (CFD/+ DEC/+). For those from FvBxBalbC, there were n=4 mice of WT and Kat6b overexpressing Transgenic genotypes. Differential expression analyses between genotype groups were performed independently for each mouse background.