Sarah Elderkin
Epigenetic gene regulation by Polycomb Repressor Complexes
Polycomb-group (PcG) repressor proteins are key epigenetic regulators involved in both establishing gene expression patterns and maintaining long-term cellular memory during development. Recently it has become clear that PcG proteins also play important roles in maintaining pluripotency of stem cells by keeping genes in an inactive, but easily inducible state. Maintenance of cellular gene expression memory by PcG proteins has been shown to be an important process in regulation of cell identity, cell proliferation and neoplastic development.
Biochemical and genetic studies have shown that PcG proteins form large multi-protein Polycomb Repressor Complexes (PRCs). The bmiPRC1 complex contains the core subunits Polycomb, Bmi1, Polyhomeotic, Ring1B and Ring1A. BmiPRC1 has recently been shown to function as an ubiquitin E3 ligase that specifically mono-ubiquitylates histone H2A lysine 119, thereby playing a key role in epigenetic gene regulation. In mammalian cells a number of different paralogues have been identified for the core PRC1 proteins. There are at least three paralogues of the Bmi1 protein; Mel-18, MBLR and NSPC1 each of which form unique PRC1-like complexes. BmiPRC1 plays a critical role in the transcriptional repression of specific genomic loci, such as the INK4a/ARF locus which encodes proteins that are involved in tumor suppression networks regulating cell senescence and apoptosis. The function and specificity of the other PRC1-like complexes and the role they play in epigenetic gene regulation is poorly understood.
Figure 1. Signalling pathways regulate transcription through epigenetic modification of Chromatin.
Recently we have characterized a novel PRC1-like complex containing the Bmi1 paralogue Mel-18 (melPRC1). We found that melPRC1 can functionally compensate for the loss of bmiPRC1 in regulation of homeotic gene expression in embryonic stem cells. In addition, phosphorylation of Mel-18 by an unidentified signalling pathway is essential for target specificity of the E3 ligase to ubiquitylate H2A. This result links cellular signalling pathways to transcriptional repression via histone modification.
The focus of our laboratory is to understand how epigenetic modification by polycomb complexes links incoming signals to ensuring the correct gene expression profiles. This is of key importance in understanding how cells integrate signals from their niche to maintain and control their correct cell identity and cell proliferation status.
Additionally we are interested in understanding the functional importance of having multiple PRC1-like complexes in the cell. In particular determining how these multiple PRC1-like complexes are recruited and recognise specific genomic loci to maintain the correct transcription profiles in mammalian cells.
Elderkin S, Maertens GN, Endoh M, Mallery DL, Morrice N, Koseki H, Peters G, Brockdorff N, Hiom K (2007) A phosphorylated form of Mel-18 targets the Ring1B histone H2A ubiquitin ligase to chromatin.
Molecular Cell 28 107-120
http://dx.doi.org/10.1016/j.molcel.2007.08.009
Kukimoto I, Elderkin S, Grimaldi M, Oelgeschlager T, Varga-Weisz PD (2004) The histone-fold protein complex CHRAC-15/17 enhances nucleosome sliding and assembly mediated by ACF.
Molecular Cell 13 265-277
http://dx.doi.org/10.1016/S1097-2765(03)00523-9
