High-throughput Oligopaint screen identifies druggable 3D genome regulators

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, Patrick J. Walsh, Richard J. Abdill, Rachel Yang, Yemin Lan, Sora Yoon, Rebecca Yunker, Masato T. Kanemaki, Golnaz Vahedi, Jennifer E. Phillips-Cremins, Rajan Jain and Eric F. Joyce ()
Additional contact information
Daniel S. Park: University of Pennsylvania
Son C. Nguyen: University of Pennsylvania
Randi Isenhart: University of Pennsylvania
Parisha P. Shah: University of Pennsylvania
Wonho Kim: University of Pennsylvania
R. Jordan Barnett: University of Pennsylvania
Aditi Chandra: University of Pennsylvania
Jennifer M. Luppino: University of Pennsylvania
Jailynn Harke: University of Pennsylvania
May Wai: University of Pennsylvania
Patrick J. Walsh: University of Pennsylvania
Richard J. Abdill: University of Pennsylvania
Rachel Yang: University of Pennsylvania
Yemin Lan: University of Pennsylvania
Sora Yoon: University of Pennsylvania
Rebecca Yunker: University of Pennsylvania
Masato T. Kanemaki: National Institute of Genetics, Research Organization of Information and Systems (ROIS)
Golnaz Vahedi: University of Pennsylvania
Jennifer E. Phillips-Cremins: University of Pennsylvania
Rajan Jain: University of Pennsylvania
Eric F. Joyce: University of Pennsylvania

Nature, 2023, vol. 620, issue 7972, 209-217

Abstract: Abstract The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions1–3. Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)—an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization.

Date: 2023
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DOI: 10.1038/s41586-023-06340-w

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