美国阿尔伯特-爱因斯坦医学院Ulrich Steidl研究团队取得一项新突破。他们研究发现使用药物破坏基因组结合位点，可重塑PU.1先驱转录因子（TF）的活性。2024年9月18日出版的《自然—遗传学》杂志发表了这项成果。

研究人员利用化学驱动的结合位点限制，实现了对先驱转录因子PU.1稳定且具有DNA序列特异性的重新分布，PU.1与许多造血恶性肿瘤的发生有关。通过一种创新技术 “CLICK-on-CUT&Tag”，研究人员描述了PU.1新的层次结构，预测了在结合位点限制下PU.1在组蛋白的分布情况。

对结合位点限制的时间和单分子研究揭示了原始PU.1的先驱动态，并发现PU.1定位于二级结合位点会诱导另一个目标基因集的矛盾激活。基因阻断和位点特异性报告实验证实了这些转录变化。结合位点限制和随后PU.1网络的重新布线，导致原代人类白血病细胞分化。总之，该研究表明可以利用药物诱导TF的重新分布，来控制TF的定位、激活交替的基因网络并控制细胞命运。

据了解，转录因子与DNA的结合动力学决定着细胞的命运和特性。然而，利用药物干预转录因子定位的能力有限。

附：英文原文

Title: Pharmacological restriction of genomic binding sites redirects PU.1 pioneer transcription factor activity

Author: Taylor, Samuel J., Stauber, Jacob, Bohorquez, Oliver, Tatsumi, Goichi, Kumari, Rajni, Chakraborty, Joyeeta, Bartholdy, Boris A., Schwenger, Emily, Sundaravel, Sriram, Farahat, Abdelbasset A., Wheat, Justin C., Goldfinger, Mendel, Verma, Amit, Kumar, Arvind, Boykin, David W., Stengel, Kristy R., Poon, Gregory M. K., Steidl, Ulrich

Issue&Volume: 2024-09-18

Abstract: Transcription factor (TF) DNA-binding dynamics govern cell fate and identity. However, our ability to pharmacologically control TF localization is limited. Here we leverage chemically driven binding site restriction leading to robust and DNA-sequence-specific redistribution of PU.1, a pioneer TF pertinent to many hematopoietic malignancies. Through an innovative technique, ‘CLICK-on-CUT&Tag’, we characterize the hierarchy of de novo PU.1 motifs, predicting occupancy in the PU.1 cistrome under binding site restriction. Temporal and single-molecule studies of binding site restriction uncover the pioneering dynamics of native PU.1 and identify the paradoxical activation of an alternate target gene set driven by PU.1 localization to second-tier binding sites. These transcriptional changes were corroborated by genetic blockade and site-specific reporter assays. Binding site restriction and subsequent PU.1 network rewiring causes primary human leukemia cells to differentiate. In summary, pharmacologically induced TF redistribution can be harnessed to govern TF localization, actuate alternate gene networks and direct cell fate.

DOI: 10.1038/s41588-024-01911-7

Source: https://www.nature.com/articles/s41588-024-01911-7