Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute of Regenerative Medicine Center of Excellence, University of California, Berkeley, Berkeley, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute of Regenerative Medicine Center of Excellence, University of California, Berkeley, Berkeley, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
Hervé Marie-Nelly
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute of Regenerative Medicine Center of Excellence, University of California, Berkeley, Berkeley, United States
Yvonne Hao
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute of Regenerative Medicine Center of Excellence, University of California, Berkeley, Berkeley, United States
Kayla K Umemoto
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; California Institute of Regenerative Medicine Center of Excellence, University of California, Berkeley, Berkeley, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
RNA Polymerase II (Pol II) and transcription factors form concentrated hubs in cells via multivalent protein-protein interactions, often mediated by proteins with intrinsically disordered regions. During Herpes Simplex Virus infection, viral replication compartments (RCs) efficiently enrich host Pol II into membraneless domains, reminiscent of liquid-liquid phase separation. Despite sharing several properties with phase-separated condensates, we show that RCs operate via a distinct mechanism wherein unrestricted nonspecific protein-DNA interactions efficiently outcompete host chromatin, profoundly influencing the way DNA-binding proteins explore RCs. We find that the viral genome remains largely nucleosome-free, and this increase in accessibility allows Pol II and other DNA-binding proteins to repeatedly visit nearby DNA binding sites. This anisotropic behavior creates local accumulations of protein factors despite their unrestricted diffusion across RC boundaries. Our results reveal underappreciated consequences of nonspecific DNA binding in shaping gene activity, and suggest additional roles for chromatin in modulating nuclear function and organization.
