Polycomb Group Complexes

PcG complexes appear to repress transcription through covalent modifications of histones (reviewed in Pasini et al. 2004, Sparmann and van Lohuizen 2006). The relationship of PcG complexes to INK4a/ARF/INK4b expression has been particularly provocative, as Bmi1 is required for stem cell maintenance of HSC (Park et al. 2003) and NSC (Molofsky et al. 2005). The ability of these complexes to create heritable epigenetic marks might suggest a nongenetic mechanism whereby cells could carry the memory of prior ageing-related exposures. At least four PcG proteins (Bmi1, Cbx7, Cbx8, and Mel18) have been reported to repress transcripts encoded by the Ink4a/Arf/Ink4b locus (p16Ink4a, p15Ink4b, and ARF) (Dietrich et al. 2007, Gil et al. 2004, Itahana et al. 2003, Jacobs et al. 1999). Loss of Bmi1 in mice is associated with failure to maintain diverse self-renewing stem cells (e.g., HSC and NSC), which can in large part be rescued by Ink4a/Arf deficiency (Bruggeman et al. 2005, Jacobs et al. 1999, Molofsky et al. 2005, Molofsky et al. 2003, Oguro et al. 2006, Park et al. 2003). In contrast, homeotic transformations of the axial skeleton noted in mice lacking Bmi1 are not rescued by loss of Ink4a/Arf (Jacobs et al. 1999). These results prove that p16INK4a and Arf are two intrinsic mediators of the stem cell exhaustion phenotype in Bmi1-deficient mice, although there is experimental evidence for additional effectors (van Lohuizen, Keystone Stem cell meeting 2007). Intriguingly, enforced expression of another PcG protein, Ezh2, in HSC has been shown to greatly augment their performance in serial transplant (Kamminga et al. 2006), further suggesting PcG complexes are limiting during stem cell ageing, at least under the stressful conditions of serial transplant.

Most recently, employing chromatin immunoprecipitation, two groups have shown that Bmi1 and Ezh2 bind to the p16INK4a promoter in human and murine cells (Bracken et al. 2007, Kotake et al. 2007). Decreased occupancy of the p16INK4a promoter by PcG proteins coincided with increased p16INK4a expression during senescence (Bracken et al. 2007). Additionally, the Bmi1 interaction with the p16INK4a promoter required Rb-family proteins (Kotake et al. 2007), suggesting an explanation for the requirement for mitogenic stimuli in the induction of senescence. In both studies and in contrast to murine cells, in human cells Bmi1 only appears to regulate the expression of p16INK4a, but not that of ARF or p15INK4b. Therefore, perhaps this mouse and human difference with regard to PcG proteins explains the marked increase with ageing in Arf expression in mice but not humans. It remains to be seen if changes in p16INK4a promoter occupancy by PcG proteins occur with mammalian ageing.

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