Center for Quantitative Biology, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Nat Commun. 2021 Mar 5;12(1):1491. doi: 10.1038/s41467-021-21690-7.
Abnormally formed FUS/EWS/TAF15 (FET) fusion oncoproteins are essential oncogenic drivers in many human cancers. Interestingly, at the molecular level, they also form biomolecular condensates at specific loci. However, how these condensates lead to gene transcription and how features encoded in the DNA element regulate condensate formation remain unclear. Here, we develop an in vitro single-molecule assay to visualize phase separation on DNA. Using this technique, we observe that FET fusion proteins undergo phase separation at target binding loci and the phase separated condensates recruit RNA polymerase II and enhance gene transcription. Furthermore, we determine a threshold number of fusion-binding DNA elements that can enhance the formation of FET fusion protein condensates. These findings suggest that FET fusion oncoprotein promotes aberrant gene transcription through loci-specific phase separation, which may contribute to their oncogenic transformation ability in relevant cancers, such as sarcomas and leukemia.
异常形成的 FUS/EWS/TAF15（FET）融合癌蛋白是许多人类癌症中必不可少的致癌驱动因子。有趣的是，在分子水平上，它们也在特定位置形成生物分子凝聚物。然而，这些凝聚物如何导致基因转录，以及 DNA 元件中编码的特征如何调节凝聚物的形成，目前仍不清楚。在这里，我们开发了一种体外单分子测定法来可视化 DNA 上的相分离。使用这项技术，我们观察到 FET 融合蛋白在靶结合位置发生相分离，相分离的凝聚物募集 RNA 聚合酶 II 并增强基因转录。此外，我们确定了可以增强 FET 融合蛋白凝聚物形成的融合结合 DNA 元件的阈值数量。这些发现表明，FET 融合癌蛋白通过特定位点的相分离促进异常基因转录，这可能有助于它们在相关癌症（如肉瘤和白血病）中的致癌转化能力。
