282502 Stability of Heterochromatin Condensation Due to Cooperative Binding

Monday, October 29, 2012: 4:07 PM
411 (Convention Center )
Peter J. Mulligan, Chemical Engineering, Stanford University, Stanford, CA, Elena F. Koslover, Biophysics Program, Stanford University, Stanford, CA and Andrew J. Spakowitz, Chemical Engineering, Biophysics, Stanford University, Stanford, CA

Gene regulation in eukaryotic cells requires the segregation of silenced genomic regions into densely packed heterochromatin, leaving the active genes in euchromatin regions more accessible. We develop a physical model that explains how such genomic states can be stably created and inherited. Epigenetic marks such as methylation at histone 3 lysine-9 (H3K9) enable chromatin condensation via bridging interactions from heterochromatin protein 1 (HP1). The underlying physical behavior can be mapped to a random-field Ising-like model with complex connectivity that accounts for the underlying chromatin structure. We use replica field theory to calculate HP1 binding for various low energy chromatin fiber structures. Each H3K9 site represents a binding site, with cooperative interactions when sites are within a contact distance. Energetic parameters are based on mononucleosome binding data. We observe phase segregation of HP1 into methylated regions, with a threshold of methylation above which we see high accumulation of HP1. This matches experimental observations that repression of heterochromatin genes occurs even with changing methylation levels. While larger differences in HP1 binding energy to H3K9me3 versus H3K9 might be expected to enhance HP1 binding in methylated regions, the differences in the dissociation constants has been found to be small. We find that smaller differences actually enhance the stability of the system to gains or losses in methylation marks and allow the cell to modulate HP1 concentration to decondense fibers for replication. Finally, we demonstrate that cooperative binding of HP1 is the key driver for HP1 accumulation into heterochromatin regions. These results match experimental observations showing strong HP1 accumulation both in vitro and in vivo. Our work presents a clear physical pathway by which epigenetic marks can control gene expression through chromatin condensation. These marks allow for behavior that is robust to methylation fluctuations, even with the addition of new histones post-replication.

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