Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China.
Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai, P. R. China.
Nucleic Acids Res. 2020 Dec 2;48(21):12135-12150. doi: 10.1093/nar/gkaa1051.
Chromatin remodeling impacts the structural neighborhoods and regulates gene expression. However, the role of enhancer-guided chromatin remodeling in the gene regulation remains unclear. Here, using RNA-seq and ChIP-seq, we identified for the first time that neurotensin (NTS) serves as a key oncogene in uveal melanoma and that CTCF interacts with the upstream enhancer of NTS and orchestrates an 800 kb chromosomal loop between the promoter and enhancer. Intriguingly, this novel CTCF-guided chromatin loop was ubiquitous in a cohort of tumor patients. In addition, a disruption in this chromosomal interaction prevented the histone acetyltransferase EP300 from embedding in the promoter of NTS and resulted in NTS silencing. Most importantly, in vitro and in vivo experiments showed that the ability of tumor formation was significantly suppressed via deletion of the enhancer by CRISPR-Cas9. These studies delineate a novel onco-enhancer guided epigenetic mechanism and provide a promising therapeutic concept for disease therapy.
染色质重塑影响结构域并调节基因表达。然而，增强子指导的染色质重塑在基因调控中的作用尚不清楚。在这里，我们首次使用 RNA-seq 和 ChIP-seq 鉴定到神经降压素 (NTS) 作为葡萄膜黑色素瘤中的关键致癌基因，并且 CTCF 与 NTS 的上游增强子相互作用，在启动子和增强子之间形成 800kb 的染色质环。有趣的是，这种新型 CTCF 指导的染色质环在一组肿瘤患者中普遍存在。此外，破坏这种染色体相互作用会阻止组蛋白乙酰转移酶 EP300 嵌入 NTS 的启动子，从而导致 NTS 沉默。最重要的是，体外和体内实验表明，通过 CRISPR-Cas9 对增强子进行缺失可显著抑制肿瘤形成的能力。这些研究描绘了一种新型的癌基因增强子指导的表观遗传机制，并为疾病治疗提供了有前途的治疗概念。
