美国宾夕法尼亚大学Robert B. Faryabi小组的论文发现了谱系决定转录因子约束内聚蛋白驱动多增强子癌基因调控。2025年12月2日出版的《Nature Cell Biology》发表了这项成果。

在套细胞淋巴瘤中，研究团队发现B细胞谱系决定因子EBF1在稀疏分布的基因周围组织了多个增强子，这些基因对B细胞的身份和肿瘤发生至关重要。时间分辨亚衍射光学追踪超过10万个染色质纤维进一步揭示了促进多增强子相互作用的不同拓扑构象。从机制上讲，课题组研究人员发现增强子在局部拓扑中心的定位是启动子参与所必需的，EBF1作为一个可渗透的屏障，阻止环挤出增强子的内聚。将这些发现扩展到T细胞白血病，研究小组发现谱系决定转录因子如EBF1和TCF1在基因位点内径向定位增强子，从而在单等位基因水平上实现多增强子对关键癌基因的调控。

研究人员表示，多个增强子调节关键基因，这些增强子通常被巨大的基因组距离分开。然而，单个染色质纤维的折叠如何使细胞类型受限的多增强子调控仍然不清楚。

附：英文原文

Title: Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation

Author: Zhou, Yeqiao, Jay, Atishay, Burget, Noah, Friedrich, Tobias, Yoon, Sora, Alsing, Jessica, Nir, Guy, Grosschedl, Rudolf, Vahedi, Golnaz, Faryabi, Robert B.

Issue&Volume: 2025-12-02

Abstract: Multiple enhancers, often separated by vast genomic distances, regulate key genes. However, how the folding of individual chromatin fibres enables cell-type-restricted multi-enhancer regulation remains unclear. Here, using acute protein degradation and time-resolved chromatin conformation capture in mantle cell lymphoma, we found that the B cell-lineage-determining factor EBF1 organizes multiple enhancers around sparsely distributed genes essential for B cell identity and oncogenesis. Time-resolved sub-diffraction optical tracing of more than 100,000 chromatin fibres further revealed diverse topological conformations that facilitate multi-enhancer interactions. Mechanistically, we discovered that enhancer positioning at local topological centres is required for promoter engagement, with EBF1 acting as a permeable barrier to loop-extruding cohesin at enhancers. Extending these findings to T cell leukaemia, we show that lineage-determining transcription factors such as EBF1 and TCF1 radially position enhancers within gene loci to enable multi-enhancer regulation of key oncogenes at the single-allele level.

DOI: 10.1038/s41556-025-01827-2

Source: https://www.nature.com/articles/s41556-025-01827-2