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Disorganization of the histone core promotes organization of heterochromatin into phase-separated droplets

S. Sanulli, MJ. Trnka, V. Dharmarajan, RW. Tibble, BD. Pascal, A. Burlingame, PR. Griffin, JD. Gross, GJ. Narlikar
doi: https://doi.org/10.1101/473132
S. Sanulli
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
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MJ. Trnka
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
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V. Dharmarajan
2Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA
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RW. Tibble
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
3Program in Chemistry and Chemical Biology, University of California San Francisco, San Francisco, CA 94158, USA
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BD. Pascal
2Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA
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A. Burlingame
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
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PR. Griffin
2Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA
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JD. Gross
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
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  • For correspondence: jdgross@cgl.ucsf.edu geeta.narlikar@ucsf.edu
GJ. Narlikar
4Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA
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  • For correspondence: jdgross@cgl.ucsf.edu geeta.narlikar@ucsf.edu
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Abstract

The heterochromatin protein HP1 is proposed to enable chromatin compaction via liquid droplet formation. Yet, a connection between phase separation and chromatin compaction has not been experimentally demonstrated. More fundamentally, how HP1 action at the level of a single nucleosome drives chromatin compaction remains poorly understood. Here we directly demonstrate that the S. pombe HP1 protein, Swi6, compacts arrays of multiple nucleosomes into phase-separated droplets. Using hydrogen-deuterium exchange, NMR, and mass-spectrometry, we further find that Swi6 substantially increases the accessibility and dynamics of buried histone residues within a mononucleosome. Restraining these dynamics via site-specific disulfide bonds impairs the compaction of nucleosome arrays into phase-separated droplets. Our results indicate that chromatin compaction and phase separation can be highly coupled processes. Further, we find that such coupling is promoted by a counter-intuitive function of Swi6, namely disorganization of the octamer core. Phase separation is canonically mediated by weak and dynamic multivalent interactions. We propose that dynamic exposure of buried histone residues increases opportunities for multivalent interactions between nucleosomes, thereby coupling chromatin compaction to phase separation. We anticipate that this new model for chromatin organization may more generally explain the formation of highly compacted chromatin assemblies beyond heterochromatin.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 18, 2018.
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Disorganization of the histone core promotes organization of heterochromatin into phase-separated droplets
S. Sanulli, MJ. Trnka, V. Dharmarajan, RW. Tibble, BD. Pascal, A. Burlingame, PR. Griffin, JD. Gross, GJ. Narlikar
bioRxiv 473132; doi: https://doi.org/10.1101/473132
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Disorganization of the histone core promotes organization of heterochromatin into phase-separated droplets
S. Sanulli, MJ. Trnka, V. Dharmarajan, RW. Tibble, BD. Pascal, A. Burlingame, PR. Griffin, JD. Gross, GJ. Narlikar
bioRxiv 473132; doi: https://doi.org/10.1101/473132

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