Repressive Polycomb-group (Pc-G) protein complexes and the counteracting Trithorax-group (Trx-G) of nucleosome remodeling factors are involved in the dynamic maintenance of proper gene expression patterns during development, acting at the level of chromatin structure. As such, they are important controllers of cell fate. When deregulated, these master switches of gene expression are strongly implicated in formation of a diverse set of cancers.

An example is the Pc-G gene Bmi1 which is overexpressed in medulloblastoma, Non small cell lung cancer, hepatocellular carcinoma, prostate cancer, breast cancer and Glioma and is causally implicated in leukemia. We and others have recently implicated Bmi1/Pc-G as a critical regulator of stem cell fate in hemapoietic stem cells, neural stem cells, mammary epithelial precursor cells and ES cells. In addition, we have shown that Bmi1 is regulated by the Shh pathway and that the Ink4a/ARF tumors suppressors are critical Bmi1 target genes in stem cells and in cancer formation. However our recent work on brain cancer (Glioma) and prostate cancer points to important ink4a/ARF-independent Bmi1 targets involved in adhesion and motility.

Comprehensive profiling of Polycomb target genes in Drosophila revealed its crucial conserved role in repressing lineage differentiation pathways and morphogens, including Wg, Hh, Delta and Notch. Using genme wide in vivo 4C on larval brains we recently demonstrated that polycomb domains interact in 3D nuclear space and are guided by chromosome architecture. Furthermore, we have characterized in detail an essential E3-ubiquitin ligase activity in the PRC1 Polycomb complex that consists of a functional Ring1B-Bmi1 heterodimer. This E3 ligase activity is required for maintenance of Polycomb repression in normal- and cancer stem cells and hence offers potential novel ways to target cancer stem cells or tumor reforming cells in which the activity of this E3 ligase is hyperactivated. This is further substantiated by a novel way by which the activity of the Ring1B.Bmi1 E3 ligase is controlled. The implications of these findings for stem cell biology, development and cancer will be discussed.