英国爱丁堡大学Abdenour Soufi和以色列希伯来大学Yosef Buganim研究团队合作取得一项新突破。他们发现核小体纤维拓扑结构引导转录因子（TFs）与增强子结合。2024年12月18日出版的《自然》发表了这项成果。

据介绍，细胞特征由多种转录因子的协同作用决定，这些转录因子与细胞类型特异性基因的增强子结合在一起。尽管转录因子能识别可及染色质中的特定DNA基团，但这一信息不足以解释转录因子如何选择增强子。

研究人员比较了能诱导不同细胞状态的四种不同TF组合，分析了TF基因组在占有率、染色质可及性、核糖体定位和核糖体分辨率水平的三维基因组结构。研究表明，单核糖体范围的结构域识别只能破译TF的单独结合。当核小体结合在一起时，TFs相互合作或竞争，以具有确定三维结构的核糖体组合为目标，其结构域具有特定模式。

在单一组合中，结构域的方向性引导TF组合沿染色质环漏斗状排列，然后横向渗入相邻的增强子。在其他组合中，TF集结在结构域密集且高度互连的环连接点上，随后转移到邻近的特异性位点。该研究提出了一种引导-搜索模型，在该模型中，核小体纤维上的结构域特征就像路标元素一样，引导TF组结合到增强子上。

附：英文原文

Title: Nucleosome fibre topology guides transcription factor binding to enhancers

Author: ODwyer, Michael R., Azagury, Meir, Furlong, Katharine, Alsheikh, Amani, Hall-Ponsele, Elisa, Pinto, Hugo, Fyodorov, Dmitry V., Jaber, Mohammad, Papachristoforou, Eleni, Benchetrit, Hana, Ashmore, James, Makedonski, Kirill, Rahamim, Moran, Hanzevacki, Marta, Yassen, Hazar, Skoda, Samuel, Levy, Adi, Pollard, Steven M., Skoultchi, Arthur I., Buganim, Yosef, Soufi, Abdenour

Issue&Volume: 2024-12-18

Abstract: Cellular identity requires the concerted action of multiple transcription factors (TFs) bound together to enhancers of cell-type-specific genes. Despite TFs recognizing specific DNA motifs within accessible chromatin, this information is insufficient to explain how TFs select enhancers1. Here we compared four different TF combinations that induce different cell states, analysing TF genome occupancy, chromatin accessibility, nucleosome positioning and 3D genome organization at the nucleosome resolution. We show that motif recognition on mononucleosomes can decipher only the individual binding of TFs. When bound together, TFs act cooperatively or competitively to target nucleosome arrays with defined 3D organization, displaying motifs in particular patterns. In one combination, motif directionality funnels TF combinatorial binding along chromatin loops, before infiltrating laterally to adjacent enhancers. In other combinations, TFs assemble on motif-dense and highly interconnected loop junctions, and subsequently translocate to nearby lineage-specific sites. We propose a guided-search model in which motif grammar on nucleosome fibres acts as signpost elements, directing TF combinatorial binding to enhancers.

DOI: 10.1038/s41586-024-08333-9

Source: https://www.nature.com/articles/s41586-024-08333-9