Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong.
Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China.
Nat Commun. 2021 Apr 14;12(1):2242. doi: 10.1038/s41467-021-22445-0.
Breast cancer is a heterogeneous disease, affecting over 3.5 million women worldwide, yet the functional role of cis-regulatory elements including super-enhancers in different breast cancer subtypes remains poorly characterized. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.
乳腺癌是一种异质性疾病，影响着全球超过 350 万名女性，然而不同乳腺癌亚型中顺式调控元件（包括超级增强子）的功能作用仍未被充分描述。三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌，预后较差。在这里，我们应用整合的表观基因组和转录组谱分析方法，揭示了乳腺癌亚型之间超级增强子的异质性，并为 TNBC 提供了具有临床相关性的生物学见解。我们使用 CRISPR/Cas9 介导的基因编辑技术，鉴定了受 TNBC 特异性超级增强子特异性调控的基因，包括 FOXC1 和 MET，从而揭示了 TNBC 中关键致癌基因特异性过表达的机制。我们还发现 ANLN 是受超级增强子调控的 TNBC 特异性基因。我们的研究揭示了 TNBC 特异性的表观基因组景观，导致了乳腺癌发生中失调的致癌基因表达。
