Biophysical Society Thematic Meeting| Les Houches 2019

Multiscale Modeling of Chromatin: Bridging Experiment with Theory

Wednesday Speaker Abstracts

HETEROCHROMATIN AND THE NUCLEAR PERIPHERY: SPECIFICITY VIA DENSITY Quinn J. MacPherson 1 ; Bruno Beltran 4 ; Andrew J Spakowitz 2,3 ; 1 Stanford University, Physics, Stanford, California, United States 2 Stanford University, Chemical Engineering, Stanford, California, United States 3 Stanford University, Materials Science, Stanford, California, United States 4 Stanford University , Biophysics, Stanford, California, United States The spatial organization of chromatin in human cells is typified by a layer of transcriptionally repressed heterochromatin adjacent to the nuclear periphery. The factors that dictate the radial organization of chromatin are important for control of transcription, cellular function, and chromatin architecture. We demonstrate that epigenetically induced density variation between heterochromatin and euchromatin in conjunction with a non-specific chromatin-lamina interaction can explain the existence of peripheral heterochromatin. We present a coarse-grained nucleosome polymer model of chromatin with beads corresponding to nucleosomes. The internucleosomal interaction depends on the measured epigenetic profile of the chromatin. Specifically, we model preferential binding of the HP1 protein to histones tails that are methylated at the ninth lysine (H3K9me3). Our bottom up approach uses experimentally measured energetics to keep the number of free parameters at a minimum. We implement internucleosomal interactions using an efficient particle-field Monte-Carlo algorithm that allows the simulation to be scaled up to chromosomal lengths. We find that the combined effect of the epigenetic state of many nucleosomes leads to a phase segregation between a chromatin-dense heterochromatic phase and a less dense euchromatic phase. The phase that each nucleosome is incorporated into is found to depend on the epigenetics many kilobase in either direction. Adding an interaction with the nuclear lamina which is equally attractive to heterochromatic and euchromatic nucleosomes results in the heterochromatin being specifically attracted to the nuclear periphery as a result of its higher density. We compare the resulting structures with microscopy, Hi-C, and Lamina Associated Domain data sets. Furthermore, we investigate the relevance of this density-based interaction on the positioning of chromosome territories.


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