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

ABSTRACT

The maintenance and functional integrity of long-term hematopoietic stem cells (LT-HSCs) is critical for lifelong hematopoietic regeneration. Histone deacetylases (HDACs) modulate 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 had shifted to the phenotypic multipotent progenitor population by 1 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 the HDAC8 protein interacts with the p53 protein and modulates p53 activity via deacetylation. Hdac8-deficient LT-HSCs displayed hyperactivation of p53 and increased apoptosis under genotoxic and hematopoietic stress. Genetic inactivation of p53 reversed the increased apoptosis and elevated expression of proapoptotic targets Noxa and Puma seen in Hdac8-deleted LT-HSCs. Dramatically compromised hematopoietic recovery and increased lethality were seen in Hdac8-deficient mice challenged with serial 5-fluorouracil treatment. This hypersensitivity to hematopoietic ablation was 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.