Abstract
Polycomb Group proteins are important epigenetic regulators of gene expression. Epigenetic control by polycomb Group proteins involves intrinsic as well as associated enzymatic activities. Polycomb target genes change with cellular context, lineage commitment and differentiation status, revealing dynamic regulation of polycomb function. It is currently unclear how this dynamic modulation is controlled and how signaling affects polycomb-mediated epigenetic processes at the molecular level. Experimental evidence on regulation of polycomb function by post-translational mechanisms is steadily emerging: Polycomb Group proteins are targeted for ubiquitylation, sumoylation and phosphorylation. In addition, specific Polycomb Group proteins modify other (chromatin) associated proteins via similar post-translational modifications. Such modifications affect protein function by affecting protein stability, protein-protein interactions and enzymatic activities. Here, we review current insights in covalent modification of Polycomb Group proteins in the context of protein function and present a tentative view of integrated signaling to chromatin in the context of phosphorylation. Clearly, the available literature reveals just the tip of the iceberg, and exact molecular mechanisms in, and the biological relevance of post-translational regulation of polycomb function await further elucidation. Our understanding of causes and consequences of post-translational modification of polycomb proteins will gain significantly from in vivo validation experiments. Impaired polycomb function has important repercussions for stem cell function, development and disease. Ultimately, increased understanding of signaling to chromatin and the mechanisms involved in epigenetic remodeling will contribute to the development of therapeutic interventions in cell fate decisions in development and disease.
Highlights
Polycomb group (PcG) proteins preserve transcriptionally silenced states through epigenetic marking of target genes in higher eukaryotes
Consistent with a functional link between MAPK signaling and Polycomb Group (PcG) function, we recently showed that PRC1/chromatin association is disrupted downstream of MAPK activation [57]
Sumoylation, GlyNAcylation and phosphorylation are probably functionally linked in PcG biology, as important cross talk between these post-translational modification (PTM) exists in many ways in other systems [84]
Summary
Polycomb group (PcG) proteins preserve transcriptionally silenced states through epigenetic marking of target genes in higher eukaryotes. Contextdependent variation in sumoylation sites is less well defined and the role of select consensus motifs in ubiquitylation is largely unknown Speculative, this may suggest that once signaling is triggered, a hierarchical sequence of PTMs is initiated, the target specificity (that is, networks, pathways, complexes) of which is defined by phosphorylation events, whereas downstream effects (among others, altered protein interactions, activity or stability) are 'merely' consequential, and controlled by numerous other PTMs. ubiquitylation, sumoylation, GlyNAcylation and phosphorylation are probably functionally linked in PcG biology, as important cross talk between these PTMs exists in many ways in other systems [84]. Notions such as these should provide important basis for future hypothesis-driven research
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