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

Area of Science:

• Hematology
• Molecular Biology
• Stem Cell Biology

Background:

• Long-term hematopoietic stem cells (LT-HSCs) are vital for lifelong blood regeneration.
• Histone deacetylases (HDACs) regulate gene expression through protein acetylation.
• HDAC8 is highly expressed in adult LT-HSCs.

Purpose of the Study:

• To investigate the role of HDAC8 in LT-HSC maintenance and function.
• To elucidate the molecular mechanisms by which HDAC8 affects LT-HSCs.
• To determine the impact of HDAC8 deficiency on hematopoietic regeneration and stress response.

Main Methods:

• Utilized Hdac8-floxed and Cre reporter mouse models.
• Assessed hematopoietic differentiation capacity in vitro and in vivo.
• Analyzed protein-protein interactions and p53 activity.
• Investigated apoptosis and gene expression under stress conditions.
• Examined hematopoietic recovery after 5-fluorouracil treatment.

Main Results:

• Hdac8 deletion led to an initial increase in LT-HSCs, followed by a shift to progenitor populations.
• Hdac8-deficient progenitors showed impaired serial replating and repopulating activity.
• HDAC8 directly interacts with and deacetylates p53, modulating its activity.
• Hdac8-deficient LT-HSCs exhibited p53 hyperactivation, increased apoptosis, and sensitivity to stress.
• p53 inactivation rescued apoptosis and improved survival in Hdac8-deficient mice under stress.

Conclusions:

• HDAC8 is essential for maintaining LT-HSC function and survival.
• HDAC8 regulates LT-HSC homeostasis by modulating p53 activity.
• Targeting HDAC8-p53 interaction may offer therapeutic strategies for hematopoietic disorders.