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Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation

View ORCID ProfileKaterina Kraft, Kathryn E. Yost, Sedona Murphy, Andreas Magg, Yicheng Long, M.Ryan Corces, Jeffrey M. Granja, Stefan Mundlos, Thomas R. Cech, Alistair Boettiger, Howard Y. Chang
doi: https://doi.org/10.1101/2020.07.27.223438
Katerina Kraft
1Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
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  • ORCID record for Katerina Kraft
Kathryn E. Yost
1Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
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Sedona Murphy
3Department of Genetics, Stanford University, Stanford, CA 94305, USA
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Andreas Magg
2RG Development & Disease, Max Planck Institute for Molecular Genetics and Institute for Medical and Human Genetics Charité Universitätsmedizin, Berlin, Germany
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Yicheng Long
4Department of Biochemistry, BioFrontiers Institute, and Howard Hughes Medical Institute, University of Colorado, Boulder, CO 80309, USA
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M.Ryan Corces
1Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
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Jeffrey M. Granja
1Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Genetics, Stanford University, Stanford, CA 94305, USA
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Stefan Mundlos
2RG Development & Disease, Max Planck Institute for Molecular Genetics and Institute for Medical and Human Genetics Charité Universitätsmedizin, Berlin, Germany
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Thomas R. Cech
4Department of Biochemistry, BioFrontiers Institute, and Howard Hughes Medical Institute, University of Colorado, Boulder, CO 80309, USA
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Alistair Boettiger
5Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA
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Howard Y. Chang
1Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
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  • For correspondence: howchang@stanford.edu
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SUMMARY

Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction1-5. This process is essential for embryonic stem cell (ESCs) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spread of H3K27me3 on the linear genome6. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remains unclear7-10. Here, we apply H3K27me3 HiChIP11-13, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture14 to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells7-10. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes, such as Hmx1, Wnt6 and Hoxa. Genetic deletion of H3K27me3 loop anchors revealed a coupling of Polycomb-associated genome architecture and H3K27me3 deposition evidenced by disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. Further, we find that global alterations in PRC2 occupancy resulting from an EZH2 mutant15 selectively deficient in RNA binding is accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 acts as a “genomic wormhole”, using RNA binding to enhance long range chromosome folding and H3K27me3 spreading. Additionally, developmental gene loci have novel roles in Polycomb spreading, emerging as important architectural elements of the epigenome.

Competing Interest Statement

H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, and an advisor to 10x Genomics, Arsenal Biosciences, and Spring Discovery. T.R.C. is a member of the board of Merck & Co., Inc., and an advisor to Storm Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation
Katerina Kraft, Kathryn E. Yost, Sedona Murphy, Andreas Magg, Yicheng Long, M.Ryan Corces, Jeffrey M. Granja, Stefan Mundlos, Thomas R. Cech, Alistair Boettiger, Howard Y. Chang
bioRxiv 2020.07.27.223438; doi: https://doi.org/10.1101/2020.07.27.223438
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Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation
Katerina Kraft, Kathryn E. Yost, Sedona Murphy, Andreas Magg, Yicheng Long, M.Ryan Corces, Jeffrey M. Granja, Stefan Mundlos, Thomas R. Cech, Alistair Boettiger, Howard Y. Chang
bioRxiv 2020.07.27.223438; doi: https://doi.org/10.1101/2020.07.27.223438

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