美国宾夕法尼亚大学Eric F. Joyce研究组发现，高通量Oligopaint筛选确定可药物靶向的三维基因组调控因子。相关论文于2023年7月12日在线发表在《自然》杂志上。

研究人员表示，人类基因组是一个三维染色质聚合物，由一系列复杂的染色体相互作用驱动。尽管支配这些相互作用的分子规则正在被迅速阐明，但调控这一过程的蛋白质却相对较少。

为了填补这一空白，研究人员开发了高通量DNA或RNA标记优化Oligopaint（HiDRO）——一种自动成像方案，能够定量测量数千个样本中单细胞的染色质相互作用。通过筛选人类可药物靶向的基因组，研究人员发现了300多个在间期影响基因组折叠的因子。其中，43个基因被证实增加或减少了拓扑关联域之间的相互作用。这些研究结果表明，对无处不在的激酶GSK3A的遗传或化学抑制会导致长程染色质环状相互作用以全基因组和黏连蛋白依赖的方式增加。这些结果证明了GSK3A信号在核结构中的重要性以及HiDRO在鉴定基因组空间组织机制中的应用。

附：英文原文

Title: High-throughput Oligopaint screen identifies druggable 3D genome regulators

Author: Park, Daniel S., Nguyen, Son C., Isenhart, Randi, Shah, Parisha P., Kim, Wonho, Barnett, R. Jordan, Chandra, Aditi, Luppino, Jennifer M., Harke, Jailynn, Wai, May, Walsh, Patrick J., Abdill, Richard J., Yang, Rachel, Lan, Yemin, Yoon, Sora, Yunker, Rebecca, Kanemaki, Masato T., Vahedi, Golnaz, Phillips-Cremins, Jennifer E., Jain, Rajan, Joyce, Eric F.

Issue&Volume: 2023-07-12

Abstract: The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions1,2,3. 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.

DOI: 10.1038/s41586-023-06340-w

Source: https://www.nature.com/articles/s41586-023-06340-w