Polycomb Repressive Complex 2 (PRC2) Restricts Hematopoietic Stem Cell Activity

Abstract

Polycomb group proteins are transcriptional repressors that play a central role in the establishment and maintenance of gene expression patterns during development. Using mice with an N-ethyl-N-nitrosourea (ENU)-induced mutation in Suppressor of Zeste 12 (Suz12), a core component of Polycomb Repressive Complex 2 (PRC2), we show here that loss of Suz12 function enhances hematopoietic stem cell (HSC) activity. In addition to these effects on a wild-type genetic background, mutations in Suz12 are sufficient to ameliorate the stem cell defect and thrombocytopenia present in mice that lack the thrombopoietin receptor (c-Mpl). To investigate the molecular targets of the PRC2 complex in the HSC compartment, we examined changes in global patterns of gene expression in cells deficient in Suz12. We identified a distinct set of genes that are regulated by Suz12 in hematopoietic cells, including eight genes that appear to be highly responsive to PRC2 function within this compartment. These data suggest that PRC2 is required to maintain a specific gene expression pattern in hematopoiesis that is indispensable to normal stem cell function. The chromatin environment that surrounds a gene heavily influences the gene's transcriptional activity. Specific modifications on histone tails serve as signposts for the basal transcriptional machinery, reflecting a cell's developmental history and identifying genes that should be actively transcribed and those that must be repressed. Polycomb group proteins are involved in large, multiprotein complexes that catalyse the post-translational modification of histones. The disruption of these complexes induces wholesale changes in gene expression, a scenario commonly seen in diseases such as cancer. We have investigated the role of Polycomb group proteins during blood cell formation: in stem cells, progenitor cells, and mature blood cells. Using a variety of functional assays, we demonstrate an important role for Polycomb group proteins in restricting the activity of hematopoietic stem cells. To define the molecular targets of the complex, we examined gene expression profiles in cells with impaired expression of Polycomb group proteins. This analysis identified a set of target genes within the hematopoietic compartment that was distinct from those defined in embryonic stem cells and fibroblasts. This study provides new insights into the role of these proteins during hematopoiesis, and suggests a novel mechanism by which they might contribute to leukaemia.