Multi-omics dissection of super-enhancer heterogeneity reveals subtype-specific transcriptional drivers in triple-negative breast cancer

IF 3 2区生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Genomics Pub Date : 2025-08-13 DOI:10.1016/j.ygeno.2025.111097

Zhilin Lu , Zhenchang Wang , Wenyong Zhu, Shuyang Cai, Xiao Sun, Hao Huang

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引用次数: 0

Abstract

As a clinically heterogeneous breast cancer subtype, triple-negative breast cancer (TNBC) currently lacks effective targeted therapies. The subtype-specific heterogeneity of tumor phenotypes and gene expression programs poses challenges for the treatment of TNBC. However, while progress has been made in understanding the epigenetic and molecular mechanisms of TNBC, studies on the role of super-enhancers (SEs) in TNBC remain limited, particularly in the exploration of preclinical models at the subtype level. This study constructed a transcriptome-driven subtype classifier for cell lines, characterized epigenetic heterogeneity in the Fudan University Shanghai Cancer Center (FUSCC) TNBC subtypes, and mapped subtype-specific super-enhancers landscape. We revealed SE-mediated regulatory mechanisms underlying subtype divergence and proposed epigenetically informed therapeutic targets. We identified ZNF703 as a regulator in the LAR subtype and NesBCL11A in the BLIS subtype, both with clinical implications. This research offers new insights into TNBC's molecular mechanisms and potential targets for subtype-specific therapies.

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超增强子异质性的多组学解剖揭示了三阴性乳腺癌中亚型特异性转录驱动因素。

三阴性乳腺癌（TNBC）作为临床上异质性的乳腺癌亚型，目前缺乏有效的靶向治疗。肿瘤表型和基因表达程序的亚型特异性异质性对TNBC的治疗提出了挑战。然而，尽管在了解TNBC的表观遗传学和分子机制方面取得了进展，但关于超级增强子（SEs）在TNBC中的作用的研究仍然有限，特别是在亚型水平上对临床前模型的探索。本研究构建了细胞系转录组驱动亚型分类器，表征了复旦大学上海肿瘤中心（FUSCC） TNBC亚型的表观遗传异质性，并绘制了亚型特异性超增强子图谱。我们揭示了se介导的亚型分化的调控机制，并提出了表观遗传信息的治疗靶点。我们发现ZNF703是LAR亚型的调节因子，NesBCL11A是BLIS亚型的调节因子，两者都具有临床意义。这项研究为TNBC的分子机制和亚型特异性治疗的潜在靶点提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genomics 生物-生物工程与应用微生物

CiteScore

9.60

自引率

2.30%

发文量

260

审稿时长

60 days

期刊介绍： Genomics is a forum for describing the development of genome-scale technologies and their application to all areas of biological investigation. As a journal that has evolved with the field that carries its name, Genomics focuses on the development and application of cutting-edge methods, addressing fundamental questions with potential interest to a wide audience. Our aim is to publish the highest quality research and to provide authors with rapid, fair and accurate review and publication of manuscripts falling within our scope.