Mechanisms of Repression by Polycomb Proteins
KeywordsPolycomb, Chromatin, Biochemistry, Methylation, Cancer
Polycomb Group Proteins maintain gene silencing throughout development and adulthood by interfering with chromatin structure. Depending on the cell type, distinct sets of genes get targeted by these proteins. How is this cell specificity established and maintained, what happen when the machinery gets awry are the main questions that we are investigating.
Polycomb Group (PcG) proteins maintain the pattern of gene expression of different cells set early during development by regulating chromatin structure. Consequently interfering with PcG proteins expression affects various biological processes such as differentiation, proliferation or maintenance of pluripotency.
Chromatin structure is defined by several parameters such as combination of histone post-translational marks, nucleosome occupancy, DNA methylation or incorporation of histone variants (figure 1). Chromatin structure contributes to the epigenetic regulation of gene expression, DNA replication or DNA repair.
PRC2, a PcG multiproteic complex is responsible for the di- and tri- methylation of histone H3 lysine 27 (figure 2). This post-translational mark is associated to parts of the genome that are either weakly transcribed or silent. The PRC2 complex is tightly regulated. Hence, it has been shown that in addition to its four core components, several cofactors (Jarid2, Pcl, AEBP2) are required for PRC2 functioning. PRC2 components are also subjected to post-translational modifications. Finally, long non-coding RNAs interact with PRC2 and might regulate its activity. How all those regulatory cues come together and orchestrate the activity of PRC2 remains unclear.
Ezh2, the catalytic subunit of PRC2, was found to be upregulated in advanced stages of prostate and breast cancer (Figure 3). Furthermore, its level of expression is correlated to poor outcome. In contrast, somatic mutations interfering with the enzymatic activity of Ezh2 were reported in subtypes of leukemia. Hence, both upregulation and inactivation of Ezh2 could have deleterious consequences. How modulating Ezh2 interferes with the tumorigenic process? Is PRC2 deregulation a leading event in this process? ...