Tuning levels of low-complexity endogenous oncogenic transcription
Tuning levels of low-complexity endogenous oncogenic transcription
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DOI：
10.1016/j.molcel.2022.04.007
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发表时间：
2022-06-02
期刊：
影响因子：
16
通讯作者：
Tjian, Robert
中科院分区：
文献类型：
--
作者：
Chong, Shasha;Graham, Thomas G. W.;Tjian, Robert
哺乳动物转录因子（TFs）的基因激活需要其低复杂性结构域（lcd）的多价相互作用，但这种相互作用如何调节转录尚不清楚。有人提出，广泛的LCD-LCD相互作用最终导致tf的液-液相分离（LLPS）是交互激活的主要机制。在这里，我们研究了调节体内LCD-LCD相互作用的数量和定位如何影响内源性人类基因的转录。定量单细胞和单分子成像显示，致癌TF EWS::FLI1需要LCD-LCD相互作用的窄优化才能激活与GGAA微卫星相关的靶基因。增加LCD - LCD对假定的LLPS的相互作用抑制患者来源细胞中这些基因的转录。同样，通过异位产生LCD-LCD相互作用，将EWS::FLI1隔离到有充分证据的LLPS隔室核核中，抑制EWS::FLI1驱动的转录和致癌转化。我们的研究结果表明，改变LCD-LCD相互作用的平衡如何影响转录调控，并提出了针对致病tf的潜在治疗策略。
Gene activation by mammalian transcription factors (TFs) requires multivalent interactions of their low complexity domains (LCDs), but how such interactions regulate transcription remains unclear. It has been proposed that extensive LCD-LCD interactions culminating in liquid-liquid phase separation (LLPS) of TFs is the dominant mechanism underlying transactivation. Here, we investigated how tuning the amount and localization of LCD-LCD interactions in vivo affects transcription of endogenous human genes. Quantitative single-cell and single-molecule imaging reveals that the oncogenic TF EWS::FLI1 requires a narrow optimum of LCD-LCD interactions to activate its target genes associated with GGAA microsatellites. Increasing LCD LCD interactions toward putative LLPS represses transcription of these genes in patient-derived cells. Likewise, ectopically creating LCD-LCD interactions to sequester EWS::FLI1 into a well-documented LLPS compartment, the nucleolus, inhibits EWS::FLI1-driven transcription and oncogenic transformation. Our findings show how altering the balance of LCD-LCD interactions can influence transcriptional regulation and suggest a potential therapeutic strategy for targeting disease-causing TFs.