Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific...

Area of Science:

• Developmental biology
• Stem cell biology
• Epigenetics

Background:

• Polycomb repressive complex 2 (PRC2) is crucial for stem cell maintenance and cancer.
• Previous studies using loss-of-function for individual PRC2 subunits yielded conflicting results.
• Eed is a core subunit essential for the assembly of PRC2 complexes containing both Ezh1 and Ezh2.

Purpose of the Study:

• To investigate the role of PRC2 in hematopoiesis by conditionally deleting the core subunit Eed.
• To determine the developmental stage-specific functions of PRC2 in hematopoietic stem cells (HSCs).

Main Methods:

• Conditional deletion of the Eed gene in mice.
• Assessment of hematopoiesis in fetal liver and adult bone marrow.
• Analysis of hematopoietic stem cell (HSC) function, including maintenance and differentiation.
• Comparative gene expression profiling of Eed-null HSCs.
• Genetic deletion of Cdkn2a in Eed-null mice.

Main Results:

• Conditional deletion of Eed leads to exhaustion of adult bone marrow HSCs.
• Fetal liver HSCs are produced in normal numbers despite Eed deletion.
• Neonatal Eed-null HSCs express HSC signature genes but exhibit defects in maintenance and differentiation.
• Gene expression profiling reveals upregulation of conflicting pathways in Eed-null HSCs.
• Deletion of Cdkn2a improves HSPC survival but does not restore HSC function in Eed-null mice.

Conclusions:

• Canonical PRC2 complexes have distinct, developmental stage-specific requirements for normal HSC function.
• Eed is essential for maintaining adult HSC function, but not for fetal HSC development.
• PRC2 regulates complex gene expression programs that are critical for HSC homeostasis.