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High-throughput Oligopaint screen identifies druggable 3D genome regulators. 2023
Daniel S Park, and
Son C Nguyen, and
Randi Isenhart, and
Parisha P Shah, and
Wonho Kim, and
R Jordan Barnett, and
Aditi Chandra, and
Jennifer M Luppino, and
Jailynn Harke, and
May Wai, and
Patrick J Walsh, and
Richard J Abdill, and
Rachel Yang, and
Yemin Lan, and
Sora Yoon, and
Rebecca Yunker, and
Masato T Kanemaki, and
Golnaz Vahedi, and
Jennifer E Phillips-Cremins, and
Rajan Jain, and
Eric F Joyce
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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.
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Jailynn Harke, and
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Patrick J Walsh, and
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