HP1 proteins compact DNA into mechanically and positionally stable phase separated domains
Madeline M Keenen,
David Brown,
Lucy D Brennan,
Roman Renger,
Harrison Khoo,
Christopher R Carlson,
Bo Huang,
Stephan W Grill,
Geeta J Narlikar,
Sy Redding
Affiliations
Madeline M Keenen
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Tetrad Graduate Program, University of California, San Francisco, San Francisco, United States
David Brown
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Lucy D Brennan
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Roman Renger
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Harrison Khoo
Department of Mechanical Engineering, Johns Hopkins University, Baltimore, United States
Christopher R Carlson
Tetrad Graduate Program, University of California, San Francisco, San Francisco, United States; Department of Physiology, University of California, San Francisco, San Francisco, United States
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States; Chan Zuckerberg Biohub, San Francisco, United States
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Cluster of Excellence Physics of Life, Technische Universität Dresden, Dresden, Germany
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Marine Biological Laboratory, Woods Hole, United States
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.
