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      HP1 proteins compact DNA into mechanically and positionally stable phase separated domains

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          Abstract

          In mammals, HP1-mediated heterochromatin forms positionally and mechanically stable genomic domains even though the component HP1 paralogs, HP1α, HP1β, and HP1γ, display rapid on-off dynamics. Here, we investigate whether phase-separation by HP1 proteins can explain these biological observations. Using bulk and single-molecule methods, we show that, within phase-separated HP1α-DNA condensates, HP1α acts as a dynamic liquid, while compacted DNA molecules are constrained in local territories. These condensates are resistant to large forces yet can be readily dissolved by HP1β. Finally, we find that differences in each HP1 paralog’s DNA compaction and phase-separation properties arise from their respective disordered regions. Our findings suggest a generalizable model for genome organization in which a pool of weakly bound proteins collectively capitalize on the polymer properties of DNA to produce self-organizing domains that are simultaneously resistant to large forces at the mesoscale and susceptible to competition at the molecular scale.

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          Most cited references78

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          Biomolecular condensates: organizers of cellular biochemistry

          In addition to membrane-bound organelles, eukaryotic cells feature various membraneless compartments, including the centrosome, the nucleolus and various granules. Many of these compartments form through liquid–liquid phase separation, and the principles, mechanisms and regulation of their assembly as well as their cellular functions are now beginning to emerge.
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            Phase Transitions in the Assembly of Multi-Valent Signaling Proteins

            Cells are organized on length scales ranging from Angstroms to microns. However, the mechanisms by which Angstrom-scale molecular properties are translated to micron-scale macroscopic properties are not well understood. Here we show that interactions between diverse, synthetic multivalent macromolecules (including multi-domain proteins and RNA) produce sharp, liquid-liquid demixing phase separations, generating micron-sized liquid droplets in aqueous solution. This macroscopic transition corresponds to a molecular transition between small complexes and large, dynamic supramolecular polymers. The concentrations needed for phase transition are directly related to valency of the interacting species. In the case of the actin regulatory protein, neuronal Wiskott-Aldrich Syndrome Protein (N-WASP) interacting with its established biological partners Nck and phosphorylated nephrin 1 , the phase transition corresponds to a sharp increase in activity toward the actin nucleation factor, Arp2/3 complex. The transition is governed by the degree of phosphorylation of nephrin, explaining how this property of the system can be controlled to regulatory effect by kinases. The widespread occurrence of multivalent systems suggests that phase transitions are likely used to spatially organize and biochemically regulate information throughout biology.
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              Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain.

              Heterochromatin protein 1 (HP1) is localized at heterochromatin sites where it mediates gene silencing. The chromo domain of HP1 is necessary for both targeting and transcriptional repression. In the fission yeast Schizosaccharomyces pombe, the correct localization of Swi6 (the HP1 equivalent) depends on Clr4, a homologue of the mammalian SUV39H1 histone methylase. Both Clr4 and SUV39H1 methylate specifically lysine 9 of histone H3 (ref. 6). Here we show that HP1 can bind with high affinity to histone H3 methylated at lysine 9 but not at lysine 4. The chromo domain of HP1 is identified as its methyl-lysine-binding domain. A point mutation in the chromo domain, which destroys the gene silencing activity of HP1 in Drosophila, abolishes methyl-lysine-binding activity. Genetic and biochemical analysis in S. pombe shows that the methylase activity of Clr4 is necessary for the correct localization of Swi6 at centromeric heterochromatin and for gene silencing. These results provide a stepwise model for the formation of a transcriptionally silent heterochromatin: SUV39H1 places a 'methyl marker' on histone H3, which is then recognized by HP1 through its chromo domain. This model may also explain the stable inheritance of the heterochromatic state.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                04 March 2021
                2021
                : 10
                : e64563
                Affiliations
                [1 ]Department of Biochemistry and Biophysics, University of California, San Francisco San FranciscoUnited States
                [2 ]Tetrad Graduate Program, University of California, San Francisco San FranciscoUnited States
                [3 ]Department of Pharmaceutical Chemistry, University of California, San Francisco San FranciscoUnited States
                [4 ]Max Planck Institute of Molecular Cell Biology and Genetics DresdenGermany
                [5 ]German Center for Neurodegenerative Diseases (DZNE) BonnGermany
                [6 ]Department of Mechanical Engineering, Johns Hopkins University BaltimoreUnited States
                [7 ]Department of Physiology, University of California, San Francisco San FranciscoUnited States
                [8 ]Chan Zuckerberg Biohub San FranciscoUnited States
                [9 ]Cluster of Excellence Physics of Life, Technische Universität Dresden DresdenGermany
                [10 ]Marine Biological Laboratory Woods HoleUnited States
                Uppsala University Sweden
                Harvard Medical School United States
                Uppsala University Sweden
                Author information
                http://orcid.org/0000-0003-1704-4141
                http://orcid.org/0000-0002-2290-5826
                https://orcid.org/0000-0002-1920-0147
                https://orcid.org/0000-0003-3463-7985
                Article
                64563
                10.7554/eLife.64563
                7932698
                33661100
                8471c762-9537-4d07-a8a7-30116e05ac93
                © 2021, Keenen et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 03 November 2020
                : 22 February 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: F31CA243360
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100008069, University of California, San Francisco;
                Award ID: Discovery Fellows Program
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: F99CA245719
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100008483, NOMIS Stiftung;
                Award ID: Graduate Student Fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: GM129652
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: GM131641
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: CA231300
                Award Recipient :
                Funded by: Chan Zuckerberg Initiative;
                Award ID: Biohub Investigator
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: SPP 1782
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: GSC 97
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: GR 3271/2
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: GR 3271/3
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: GR 3271/4
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100010663, H2020 European Research Council;
                Award ID: 742712
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: GM127020
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;
                Award ID: 1921794
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100008069, University of California, San Francisco;
                Award ID: Program for Breakthrough Biomedical Research
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006049, Marine Biological Laboratory;
                Award ID: Whitman Fellowship
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Biochemistry and Chemical Biology
                Structural Biology and Molecular Biophysics
                Custom metadata
                Heterochromatin proteins compartmentalize DNA into compact structures resistant to mechanical disruption but susceptible to competitive dissolution.

                Life sciences
                heterochromatin,phase separation,chromatin organization,human
                Life sciences
                heterochromatin, phase separation, chromatin organization, human

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