TWIST2-Mediated Chromatin Remodeling Promotes Fusion-Negative Rhabdomyosarcoma [ChIP-seq]

Sarcomas are derailed in pathways that specify mesenchymal lineages during embryogenesis, causing tumor cells to stall at early stages of differentiation. Among them, rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma of skeletal muscle origin. A key feature of RMS is their inability to terminally differentiate despite the high expression of master myogenic regulator MYOD. The bHLH transcription factor TWIST2, which governs mesenchymal stem cell identity and restricts myogenesis, is overexpressed in patient fusion-negative RMS (FN-RMS) tumors. We show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo myogenic differentiation, thereby reducing the growth of FN-RMS xenograft tumors. ChIP-seq analysis revealed that most TWIST2-mediated gene regulation occurs independent of changes in MYOD binding in FN-RMS cells. Instead, TWIST2 controls the deposition of H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers, SMARCA4 and CHD3, to activate growth-related and repress myogenesis-related TWIST2 target genes. Our findings provide new insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the clinical potential of reversing the TWIST2-regulated phenotype. NOT PROVIDED; REQUESTED

肉瘤在胚胎发育期间调控间质谱系的通路中发生紊乱，致使肿瘤细胞停滞于分化早期阶段。其中，横纹肌肉瘤（rhabdomyosarcoma, RMS）是一类起源于骨骼肌的儿童软组织肉瘤。横纹肌肉瘤的一个关键特征是，尽管肌源性主调控因子MYOD呈高表达，其肿瘤细胞仍无法完成终末分化。碱性螺旋-环-螺旋（bHLH）转录因子TWIST2可调控间质干细胞特性并抑制肌发生，在融合阴性横纹肌肉瘤（fusion-negative RMS, FN-RMS）患者肿瘤组织中呈过表达状态。本研究证实，敲低TWIST2可使FN-RMS细胞退出细胞周期并启动肌源性分化，进而抑制FN-RMS异种移植瘤的生长。染色质免疫共沉淀测序（ChIP-seq）分析显示，在FN-RMS细胞中，绝大多数由TWIST2介导的基因调控并不依赖于MYOD结合的改变。相反，TWIST2可通过与染色质重塑因子SMARCA4及CHD3相互作用，调控远端增强子区域的H3K27乙酰化修饰水平，从而激活与生长相关的靶基因并抑制与肌发生相关的靶基因。本研究结果为TWIST2在维持FN-RMS未分化及致瘤状态中的作用提供了新见解，并揭示了逆转TWIST2调控表型的临床应用潜力。未提供，敬请索取