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Capturing the onset of PRC2-mediated repressive domain formation

Ozgur Oksuz, Varun Narendra, Chul-Hwan Lee, Nicolas Descostes, Gary LeRoy, Ramya Raviram, Lili Blumenberg, Kelly Karch, Pedro R. Rocha, Benjamin A. Garcia, Jane A. Skok, Danny Reinberg
doi: https://doi.org/10.1101/272989
Ozgur Oksuz
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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Varun Narendra
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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Chul-Hwan Lee
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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Nicolas Descostes
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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Gary LeRoy
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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Ramya Raviram
3Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
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Lili Blumenberg
3Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
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Kelly Karch
4Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Pedro R. Rocha
3Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
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Benjamin A. Garcia
4Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Jane A. Skok
3Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
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Danny Reinberg
1Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA
2Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
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  • For correspondence: Danny.Reinberg@nyumc.org
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Summary

Polycomb repressive complex 2 (PRC2) maintains gene silencing by catalyzing methylation of histone H3 at lysine 27 (H3K27me2/3) within chromatin. By designing a system whereby PRC2-mediated repressive domains were collapsed and then reconstructed in an inducible fashion in vivo, a two-step mechanism of H3K27me2/3 domain formation became evident. First, PRC2 is stably recruited by the actions of JARID2 and MTF2 to a limited number of spatially interacting “nucleation sites”, creating H3K27me3-forming polycomb foci within the nucleus. Second, PRC2 is allosterically activated via its binding to H3K27me3 and rapidly spreads H3K27me2/3 both in cis and in far-cis via long-range contacts. As PRC2 proceeds further from the nucleation sites, its stability on chromatin decreases such that domains of H3K27me3 remain proximal, and those of H3K27me2 distal, to the nucleation sites. This study demonstrates the principles of de novo establishment of PRC2-mediated repressive domains across the genome.

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Posted February 27, 2018.
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Capturing the onset of PRC2-mediated repressive domain formation
Ozgur Oksuz, Varun Narendra, Chul-Hwan Lee, Nicolas Descostes, Gary LeRoy, Ramya Raviram, Lili Blumenberg, Kelly Karch, Pedro R. Rocha, Benjamin A. Garcia, Jane A. Skok, Danny Reinberg
bioRxiv 272989; doi: https://doi.org/10.1101/272989
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Capturing the onset of PRC2-mediated repressive domain formation
Ozgur Oksuz, Varun Narendra, Chul-Hwan Lee, Nicolas Descostes, Gary LeRoy, Ramya Raviram, Lili Blumenberg, Kelly Karch, Pedro R. Rocha, Benjamin A. Garcia, Jane A. Skok, Danny Reinberg
bioRxiv 272989; doi: https://doi.org/10.1101/272989

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