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Interrogation of the Dynamic Properties of Higher-Order Heterochromatin Using CRISPR/dCas9

Yuchen Gao, Mengting Han, Stephen Shang, Haifeng Wang, View ORCID ProfileLei S. Qi
doi: https://doi.org/10.1101/2021.06.06.447300
Yuchen Gao
1Cancer Biology Program; Stanford University, Stanford, CA 94305, USA
2Department of Bioengineering; Stanford University, Stanford, CA 94305, USA
5Mammoth Biosciences, Brisbane, CA, 94005, USA
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Mengting Han
2Department of Bioengineering; Stanford University, Stanford, CA 94305, USA
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Stephen Shang
2Department of Bioengineering; Stanford University, Stanford, CA 94305, USA
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Haifeng Wang
2Department of Bioengineering; Stanford University, Stanford, CA 94305, USA
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Lei S. Qi
2Department of Bioengineering; Stanford University, Stanford, CA 94305, USA
3Department of Chemical and Systems Biology; Stanford University, Stanford, CA 94305, USA
4ChEM-H; Stanford University, Stanford, CA 94305, USA
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  • ORCID record for Lei S. Qi
  • For correspondence: stanley.qi@stanford.edu
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ABSTRACT

Eukaryotic chromosomes feature large regions of compact, repressed heterochromatin hallmarked by Heterochromatin Protein 1 (HP1). HP1 proteins play multi-faceted roles in shaping heterochromatin, and in cells, HP1 tethering to individual gene promoters leads to epigenetic modifications and silencing. However, emergent properties of HP1 at supranucleosomal scales remain difficult to study in cells due to lack of appropriate tools. Here, we develop CRISPR-Engineered Chromatin Organization (EChO), combining live cell CRISPR imaging with inducible large-scale recruitment of chromatin proteins to native genomic targets. We demonstrate that human HP1α tiling across kilobase-scale genomic DNA forms novel contacts with natural heterochromatin, integrates two distantly targeted regions, and reversibly changes chromatin from a diffuse to compact state. The compact state exhibits delayed disassembly kinetics and represses transcription across over 600 kilobases. These findings support a polymer model of HP1α-mediated chromatin regulation and highlight the utility of CRISPR-EChO in studying supranucleosomal chromatin organization in living cells.

Competing Interest Statement

The authors have filed a U.S. Provisional Application (No. 62/744,504) via Stanford University.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 07, 2021.
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Interrogation of the Dynamic Properties of Higher-Order Heterochromatin Using CRISPR/dCas9
Yuchen Gao, Mengting Han, Stephen Shang, Haifeng Wang, Lei S. Qi
bioRxiv 2021.06.06.447300; doi: https://doi.org/10.1101/2021.06.06.447300
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Interrogation of the Dynamic Properties of Higher-Order Heterochromatin Using CRISPR/dCas9
Yuchen Gao, Mengting Han, Stephen Shang, Haifeng Wang, Lei S. Qi
bioRxiv 2021.06.06.447300; doi: https://doi.org/10.1101/2021.06.06.447300

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