HDAC8 regulates long-term hematopoietic stem-cell maintenance under stress by modulating p53 activity

The maintenance and functional integrity of long-term hematopoietic stem cells (LT-HSC) is critical for lifelong hematopoietic regeneration. Histone deacetylases (HDAC) modulates acetylation of lysine residues, a protein modification important for regulation of numerous biological processes. Here, we show that Hdac8 is most highly expressed in the phenotypic LT-HSC population within the adult hematopoietic hierarchy. Using an Hdac8-floxed allele and a dual fluorescence Cre reporter allele, largely normal hematopoietic differentiation capacity of Hdac8-deficient cells was observed. However, the frequency of phenotypic LT-HSC population was significantly higher shortly after Hdac8 deletion and the expansion shifted to the phenotypic multipotent progenitor population by one year. We show that Hdac8-deficient hematopoietic progenitors are compromised in colony-forming cell serial-replating in vitro and long-term serial-repopulating activity in vivo. Mechanistically, we demonstrate that Hdac8 protein interacts with the p53 protein and modulates p53 activity via deacetylation. Hdac8-deficient LT-HSCs display hyperactivation of p53 and increased apoptosis under genotoxic and hematopoietic stress. Genetic inactivation of p53 reversed the increased apoptosis and elevated expression of pro-apoptotic targets Noxa and Puma seen in Hdac8-deleted LT-HSCs. Dramatically compromised hematopoietic recovery and increased lethality was seen in Hdac8-deficient mice challenged with serial 5-fluorouracil treatment. This hypersensitivity to hematopoietic ablation is completely rescued by inactivation of p53. Altogether, these results indicate that Hdac8 functions to modulate p53 activity to ensure LT-HSC maintenance and cell survival under stress.