Human silencers have been shown to regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form ‘super-silencers’ and whether they are linked to cancer progression. Here, we show two silencer components of the FGF18 gene can cooperate through compensatory chromatin interactions to form a super-silencer. Double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes in cell identity. To perturb the super-silencers, we applied combinational treatment of an enhancer of zeste homolog 2 inhibitor GSK343, and a repressor element 1-silencing transcription factor inhibitor, X5050 (‘GR’). Interestingly, GR led to severe loss of topologically associated domains and loops, which were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GR synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects in vivo. Overall, our data demonstrated a super-silencer example and showed that GR can disrupt super-silencers, potentially leading to cancer ablation.

人类沉默剂已被证明可以调节发育基因表达。然而，人类消音器的功能重要性需要阐明，例如它们是否可以形成“超级消音器”以及它们是否与癌症进展有关。在这里，我们展示了FGF18基因的两个沉默子组件可以通过补偿性染色质相互作用合作形成超级沉默子。两个沉默子的双敲除表现出FGF18表达的协同上调和细胞身份的变化。为了扰乱超级沉默子，我们应用了 zeste 同源物 2 增强子抑制剂 GSK343 和阻遏元件 1 沉默转录因子抑制剂 X5050 ('GR') 的组合治疗。有趣的是，GR 导致拓扑相关结构域和环的严重丢失，这与CTCF和TOP2A mRNA 水平降低有关。此外，GR协同上调与细胞周期、细胞凋亡和DNA损伤相关的超级沉默子控制基因，从而在体内产生抗癌作用。总的来说，我们的数据展示了一个超级消音器的例子，并表明 GR 可以破坏超级消音器，可能导致癌症消融。