Submitted April 18, 2008
Accepted February 21, 2009
The HAT activity of MOZ is critical for the proliferation of hematopoietic precursors
Flor M. Perez-Campo, Julian Borrow, Valerie Kouskoff, and Georges Lacaud*
Cancer Research UK Stem Cell Biology Group, Paterson Institute for Cancer Research, The University of Manchester, Manchester, United Kingdom
West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, United Kingdom
Cancer Research UK Stem Cell Haematopoiesis Group, Paterson Institute for Cancer Research, The University of Manchester, Manchester, United Kingdom
* Corresponding author; email: glacaud{at}picr.man.ac.uk.
The Monocytic leukaemia Zinc finger (MOZ) gene encodes a large multi-domain protein that contains, besides other domains, two co-activation domains for the transcription factor Runx1/AML1 and a Histone Acetyl transferase (HAT) catalytic domain. Recent studies have demonstrated the critical requirement for the complete MOZ protein in hematopoietic stem cell development and maintenance. However, the specific function of the HAT activity of MOZ remains unknown as it has been shown that MOZ HAT activity is not required either for its role as Runx1 co-activator or for the leukemic transformation induced by MOZ-TIF2. To assess the specific requirement for this HAT activity during hematopoietic development, we have generated ES cells and mouse lines carrying a point mutation that renders the protein catalytically inactive. We report here that mice exclusively lacking the HAT activity of MOZ exhibit significant defects in the number of hematopoietic stem cells (HSCs) and hematopoietic committed precursors as well as defect in B cell development. Furthermore, we demonstrate that the failure to maintain a normal number of hematopoietic precursors is caused by the inability of HAT-/- cells to expand. These results indicate a specific role of MOZ-driven acetylation in controlling a desirable balance between proliferation and differentiation during hematopoiesis.
