(261g) Theoretical Model for HP1-Induced Heterochromatin Formation

Gene regulation in eukaryotes requires the segregation of silenced genomic regions into densely packed heterochromatin, leaving the active genes in euchromatin regions more accessible.  The stable maintenance of this process is critical for ensuring proper cell differentiation, and is present in organisms from yeast to humans.  We introduce a model that connects the presence of epigenetically inherited histone marks, tri-methylation at histone 3 lysine-9 (H3K9), to the physical compaction of chromatin fibers via the binding of heterochromatin protein 1 (HP1).  Using a model based on the mechanical properties of the DNA and the steric interactions of the DNA and nucleosomes, we generate optimized chromatin-fiber structures, which lay out the spatial positions of the H3K9 sites (1).  Our model demonstrates some of the key physical features that are necessary to explain several experimental observations, including the phase segregation of heterochromatin regions and the increased HP1 concentration in these regions (2).  Since each site within these arrays can be either methylated or unmethylated, the binding of HP1 will be affected not only by the total methylation level but also by the specific methylation profile for a given array.  Calculation of the quenched average over all these profiles reveals increased fluctuations and a rising of the minimum interaction strength necessary to form a stable heterochromatin phase. We also explore under what circumstances there is a threshold of methylation over which the fibers will compact; this threshold provides a buffer against small losses of methylation such as occur during cell division (3).  Finally, by extracting our model parameters from recent in vitro experiments, we find the biologically relevant HP1 concentrations that are needed to maintain the segregation of HP1 into highly methylated regions (4).  Many of the observations that we make about the HP1 system are guided by general thermodynamics principles and thus could play a role in other DNA organizational processes such as the binding of linker histones.

¹Koslover, Elena et al. (2010) Biophys J, 99.

²Muller, Katharina et al. (2009) Biophys J, 97.

³Xu, Mo et al. (2012) EMBO Reports, 13.

⁴Canzio, Daniele et al. (2011) Molec Cell, 41.