Genome-wide maps of transcriptomic and epigenomic state in melanoma cell lines

A mechanistic relationship between tumor epigenetic plasticity and nongenetic adaptive resistance to therapy is described, with MAPK inhibition of BRAF-mutant melanoma cells providing the model system. Upon inhibition, these largely melanocytic cells undergo reversible cell-state changes, ultimately yielding a drug-resistant mesenchymal-like phenotype. Epigenomic and transcriptomic kinetic studies, coupled with information theory and dynamic system modeling, revealed that, after just 3-days of treatment, RelA drives chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. Specifically, RelA transcriptionally inhibits SOX10 and NFKBIE through recruiting KDM5B and HDAC1 to down-regulate histone marks H3K4me3 and H3K27ac at their promoter regions. Suppression of SOX10 mediates melanoma regression towards drug-refractory phenotypes. These findings were confirmed in melanoma patients under MAPK inhibitor treatment, providing mechanistic insights into resistance-leading epigenetic reprogramming triggered following drug exposure. Examination of 2 different histone modifications and chromatin accessibility and transcriptome in melanoma cell lines

本研究阐明了肿瘤表观遗传可塑性（epigenetic plasticity）与治疗相关性非遗传性适应性耐药之间的机制关联，并以BRAF突变型黑色素瘤细胞的MAPK（丝裂原活化蛋白激酶）抑制模型作为研究体系。在接受MAPK抑制处理后，这类以黑色素细胞表型为主的细胞会发生可逆的细胞状态转变，最终形成耐药性的间充质样表型。通过表观基因组学（epigenomics）与转录组学（transcriptomics）的动力学研究，结合信息论与动态系统建模分析，团队发现仅在药物处理3天后，转录因子RelA即可介导染色质重塑（chromatin remodeling），进而建立一套编码长期表型改变的表观遗传程序。具体而言，RelA通过招募KDM5B与HDAC1，在SOX10与NFKBIE的启动子区域下调组蛋白修饰标记H3K4me3与H3K27ac，从而对二者实现转录抑制。SOX10的表达抑制可介导黑色素瘤细胞向药物难治性表型转化。上述研究结果在接受MAPK抑制剂治疗的黑色素瘤患者队列中得到验证，为药物暴露后触发的、可导致耐药的表观遗传重编程（epigenetic reprogramming）机制提供了深入解析。本研究对黑色素瘤细胞系中的两种不同组蛋白修饰、染色质开放状态以及转录组开展了检测分析。