Enhancer Reprogramming within Pre-existing Topologically Associated Domains Promotes TGF-β-Induced EMT and Cancer Metastasis
Enhancer Reprogramming within Pre-existing Topologically Associated Domains Promotes TGF-β-Induced EMT and Cancer Metastasis
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预先存在的拓扑相关域内的增强子重编程促进 TGF-β 诱导的 EMT 和癌症转移。
DOI：
10.1016/j.ymthe.2020.05.026
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发表时间：
2020-09-02
影响因子：
12.4
通讯作者：
Zhong, Guisheng
中科院分区：
文献类型：
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作者：
Qiao, Yunbo;Wang, Zejian;Zhong, Guisheng
转录生长因子β（TGF-β）信号触发的上皮-间质转化（EMT）过程与肿瘤的干化、转移和化疗耐药性相关。然而，TGF-β诱导的EMT的表观基因组学基础在很大程度上仍然未知。在这里，我们揭示了HDAC1介导的全局组蛋白去乙酰化和特定组蛋白H3赖氨酸27乙酰化（H3K27ac）标记的增强子的获得对于TGF-β诱导的EMT过程至关重要。TGF-β治疗后获得的增强子与EMT标志物的基因激活和癌症转移有关。值得注意的是，动态增强子的获得或丢失主要发生在上皮细胞中预先存在的拓扑相关结构域（TADs）内，具有最小的三维（3D）基因组结构重组。通过对TGF-β刺激后丢失或获得的增强子的基序富集分析，我们确定FOXA 2是激活上皮特异性增强子活性的关键因子，并且我们还发现TEAD 4与SMAD 2/3形成复合物来介导TGF-β信号传导触发的间充质增强子重编程。总之，我们的研究结果表明，关键转录因子（TF）介导的增强子重编程调节TGF-β信号相关的癌症转移的发育转变。
Transcription growth factor beta (TGF-beta) signaling-triggered epithelial-to-mesenchymal transition (EMT) process is associated with tumor stemness, metastasis, and chemotherapy resistance. However, the epigenomic basis for TGF-beta-induced EMT remains largely unknown. Here we reveal that HDAC1-mediated global histone deacetylation and the gain of specific histone H3 lysine 27 acetylation (H3K27ac)-marked enhancers are essential for the TGF-beta-induced EMT process. Enhancers gained upon TGF-beta treatment are linked to gene activation of EMT markers and cancer metastasis. Notably, dynamic enhancer gain or loss mainly occurs within pre-existing topologically associated domains (TADs) in epithelial cells, with minimal three-dimensional (3D) genome architecture reorganization. Through motif enrichment analysis of enhancers that are lost or gained upon TGF-beta stimulation, we identify FOXA2 as a key factor to activate epithelial-specific enhancer activity, and we also find that TEAD4 forms a complex with SMAD2/3 to mediate TGF-beta signaling-triggered mesenchymal enhancer reprogramming. Together, our results implicate that key transcription-factor (TF)-mediated enhancer reprogramming modulates the developmental transition in TGF-beta signaling-associated cancer metastasis.