Phase separation directs ubiquitination of gene-body nucleosomes

Laura D. Gallego, Maren Schneider, Chitvan Mittal, Anete Romanauska, Ricardo M. Gudino Carrillo, Tobias Schubert, B. Franklin Pugh and Alwin Köhler ()
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Laura D. Gallego: Medical University of Vienna, Vienna Biocenter Campus (VBC)
Maren Schneider: Medical University of Vienna, Vienna Biocenter Campus (VBC)
Chitvan Mittal: Pennsylvania State University
Anete Romanauska: Medical University of Vienna, Vienna Biocenter Campus (VBC)
Ricardo M. Gudino Carrillo: Medical University of Vienna, Vienna Biocenter Campus (VBC)
Tobias Schubert: Medical University of Vienna, Vienna Biocenter Campus (VBC)
B. Franklin Pugh: Pennsylvania State University
Alwin Köhler: Medical University of Vienna, Vienna Biocenter Campus (VBC)

Nature, 2020, vol. 579, issue 7800, 592-597

Abstract: Abstract The conserved yeast E3 ubiquitin ligase Bre1 and its partner, the E2 ubiquitin-conjugating enzyme Rad6, monoubiquitinate histone H2B across gene bodies during the transcription cycle1. Although processive ubiquitination might—in principle—arise from Bre1 and Rad6 travelling with RNA polymerase II2, the mechanism of H2B ubiquitination across genic nucleosomes remains unclear. Here we implicate liquid–liquid phase separation3 as the underlying mechanism. Biochemical reconstitution shows that Bre1 binds the scaffold protein Lge1, which possesses an intrinsically disordered region that phase-separates via multivalent interactions. The resulting condensates comprise a core of Lge1 encapsulated by an outer catalytic shell of Bre1. This layered liquid recruits Rad6 and the nucleosomal substrate, which accelerates the ubiquitination of H2B. In vivo, the condensate-forming region of Lge1 is required to ubiquitinate H2B in gene bodies beyond the +1 nucleosome. Our data suggest that layered condensates of histone-modifying enzymes generate chromatin-associated ‘reaction chambers’, with augmented catalytic activity along gene bodies. Equivalent processes may occur in human cells, and cause neurological disease when impaired.

Date: 2020
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DOI: 10.1038/s41586-020-2097-z

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