The roles of the acetyltransferase domains of the chromatin regulators KAT6A and KAT6B in vivo.

KAT6A (MOZ) and KAT6B (QKF/MORF) are related histone lysine acetyltransferases (KATs) that have a high degree of functional redundancy during development. In the absence of KAT6A, embryos undergo an anterior homeotic transformation of the axial skeleton, develop an interrupted aortic arch, have ventricular septal defects and fail to form definitive hematopoietic stem cells. KAT6B has roles in brain, skeletal and hematopoietic system development. Because loss of KAT6A leads to highly penetrant phenotypes, this allows us to determine whether the acetylation function is essential for all activities. We show that loss of acetyltransferase activity did not phenocopy the loss of the KAT6A protein in mice. Although mutation of the KAT domains of both KAT6A and KAT6B together increased the severity of phenotypes observed, these were milder than complete KAT6A loss of function. KAT domain mutants displayed ventricular septal defects and reduced (but not eliminated) hematopoietic stem cell activity. However, they did not display homeotic transformations or aortic arch defects, suggesting that, while acetylation is important for some functions, others can proceed without this activity. Accordingly, KAT6 proteins appear to have functions beyond acetylation.