Polycomb group genes: keeping stem cell activity in balance

Abstract

Overexpression of Polycomb group genes is often associated with cancer development, whereas complete deletion results in loss of stem cell activity. New studies show that partial loss of function of Polycomb group genes enhances the activity of blood stem/progenitor cells.

Figure 1. Nucleosome Crystal Structure and Potential Effect of Mono-Ubiquinated H2A on Chromatin Accessibility

(A) Representation of the nucleosome crystal structure at 2.8 Å resolution (Protein Data Bank #1AOI) [31]. The histone octamer (in grey) is complexed with 146 base pairs of DNA (red). The histone H3 lysine 27 (blue) located on the N-terminal tail is tri-methylated (H3K27me3) by the PRC2 complex. The histone H2A lysine 119 (green), which is mono-ubiquitylated (uH2AK119) by the PRC1 complex, is located near the entry and exit point of DNA on the histone octamer. (B) In accordance with recent studies, the nucleosome structure shows that, because of their location at the entry and exit point of DNA, ubiquitin molecules (beige) bound to H2AK119 could maintain genes in a repressed state by limiting the access of the RNA polII to chromatin [11]. Interestingly, ubiquitinated H2AK119 is also located at the linker-histone H1 binding region. Studies have shown that uH2AK119 enhances histone H1 interaction with the nucleosome [12,13], suggesting that this epigenetic modification is important for maintaining the compacted chromatin structure.

Figure 2. Model for Gene Dosage Effect of PcG Genes on Stem Cells and Cancer

Adequate PcG gene levels, such as in wild-type cells (+/+), seem to be crucial for normal stem cell functions. Either overexpression (+++) or partial loss of function (+/−) of PcG genes leads to an increase in tumor development. In turn, complete ablation (−/−) is detrimental and leads to impairment or loss of stem cells.