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Dynamical modeling of the H3K27 epigenetic landscape in mouse embryonic stem cells.
PLoS Comput Biol, 18(9):e1010450.
The Polycomb system via the methylation of the lysine 27 of histone H3 (H3K27)plays central roles in the silencing of many lineage-specific genes duringdevelopment. Recent experimental evidence suggested that the recruitment ofhistone modifying enzymes like the Polycomb repressive complex 2 (PRC2) atspecific sites and their spreading capacities from these sites are key to theestablishment and maintenance of a proper epigenomic landscape aroundPolycomb-target genes. Here, to test whether such mechanisms, as a minimal set ofqualitative rules, are quantitatively compatible with data, we developed amathematical model that can predict the locus-specific distributions of H3K27modifications based on previous biochemical knowledge. Within the biologicalcontext of mouse embryonic stem cells, our model showed quantitative agreementwith experimental profiles of H3K27 acetylation and methylation aroundPolycomb-target genes in wild-type and mutants. In particular, we demonstratedthe key role of the reader-writer module of PRC2 and of the competition betweenthe binding of activating and repressing enzymes in shaping the H3K27 landscapearound transcriptional start sites. The predicted dynamics of establishment andmaintenance of the repressive trimethylated H3K27 state suggest a slowaccumulation, in perfect agreement with experiments. Our approach represents afirst step towards a quantitative description of PcG regulation in variouscellular contexts and provides a generic framework to better characterizeepigenetic regulation in normal or disease situations.
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