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High-throughput Oligopaint screen identifies druggable regulators of genome folding

Daniel S. Park, Son C. Nguyen, Randi Isenhart, Parisha P. Shah, Wonho Kim, R. Jordan Barnett, Aditi Chandra, Jennifer M. Luppino, Jailynn Harke, May Wai, Rachel Yang, Yemin Lan, Sora Yoon, Rebecca Yunker, Golnaz Vahedi, Jennifer E. Phillips-Cremins, Rajan Jain, Eric F. Joyce
doi: https://doi.org/10.1101/2022.04.08.487672
Daniel S. Park
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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Son C. Nguyen
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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Randi Isenhart
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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Parisha P. Shah
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
3Department of Cell and Developmental Biology, Department of Medicine, Institute of Regenerative Medicine, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Wonho Kim
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
3Department of Cell and Developmental Biology, Department of Medicine, Institute of Regenerative Medicine, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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R. Jordan Barnett
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
4Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
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Aditi Chandra
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
5Institute for Immunology, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
6Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
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Jennifer M. Luppino
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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Jailynn Harke
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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May Wai
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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Rachel Yang
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
3Department of Cell and Developmental Biology, Department of Medicine, Institute of Regenerative Medicine, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Yemin Lan
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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Sora Yoon
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
5Institute for Immunology, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
6Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
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Rebecca Yunker
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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Golnaz Vahedi
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
5Institute for Immunology, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
6Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
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Jennifer E. Phillips-Cremins
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
4Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
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Rajan Jain
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
3Department of Cell and Developmental Biology, Department of Medicine, Institute of Regenerative Medicine, Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Eric F. Joyce
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
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  • For correspondence: erjoyce@upenn.edu
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Summary

Although the molecular rules governing genome organization are being quickly elucidated, relatively few proteins regulating this process have been identified. To address this gap, we developed a fully automated imaging pipeline, called HiDRO (high-throughput DNA or RNA labeling with optimized Oligopaints), that permits quantitative measurement of chromatin interactions across a large number of samples. Using HiDRO, we screened the human druggable genome and identified >300 factors that regulate chromatin folding during interphase, including 43 validated hits that either increase or decrease interactions between topological associating domains (TADs). We discovered that genetic or chemical inhibition of the ubiquitous kinase GSK3A enhances long-range interactions by dysregulating cohesin-mediated chromatin looping. Collectively, these results highlight a noncanonical role for GSK3A signaling in nuclear architecture and underscore the broader utility of HiDRO-based screening to identify novel mechanisms that drive the spatial organization of the genome.

Competing Interest Statement

The authors have declared no competing interest.

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-NC-ND 4.0 International license.
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Posted April 10, 2022.
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High-throughput Oligopaint screen identifies druggable regulators of genome folding
Daniel S. Park, Son C. Nguyen, Randi Isenhart, Parisha P. Shah, Wonho Kim, R. Jordan Barnett, Aditi Chandra, Jennifer M. Luppino, Jailynn Harke, May Wai, Rachel Yang, Yemin Lan, Sora Yoon, Rebecca Yunker, Golnaz Vahedi, Jennifer E. Phillips-Cremins, Rajan Jain, Eric F. Joyce
bioRxiv 2022.04.08.487672; doi: https://doi.org/10.1101/2022.04.08.487672
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High-throughput Oligopaint screen identifies druggable regulators of genome folding
Daniel S. Park, Son C. Nguyen, Randi Isenhart, Parisha P. Shah, Wonho Kim, R. Jordan Barnett, Aditi Chandra, Jennifer M. Luppino, Jailynn Harke, May Wai, Rachel Yang, Yemin Lan, Sora Yoon, Rebecca Yunker, Golnaz Vahedi, Jennifer E. Phillips-Cremins, Rajan Jain, Eric F. Joyce
bioRxiv 2022.04.08.487672; doi: https://doi.org/10.1101/2022.04.08.487672

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