Wang Shengyuan, Wang Zhenjia, Zang Chongzhi
Department of Genome Sciences, University of Virginia, PO Box 800717, Charlottesville, VA 22908, USA.
Department of Biochemistry and Molecular Genetics, University of Virginia, PO Box 800733, Charlottesville, VA 22908, USA.
Nucleic Acids Res. 2025 Jan 24;53(3). doi: 10.1093/nar/gkaf015.
Many transcription factors (TFs) have been shown to bind to super-enhancers, forming transcriptional condensates to activate transcription in various cellular systems. However, the genomic and epigenomic determinants of phase-separated transcriptional condensate formation remain poorly understood. Questions regarding which TFs tend to associate with transcriptional condensates and what factors influence their association are largely unanswered. Here we systematically analyzed 571 DNA sequence motifs across the human genome and 6650 TF binding profiles across different cell types to identify the molecular features contributing to the formation of transcriptional condensates. We found that the genomic distributions of sequence motifs for different TFs exhibit distinct clustering tendencies. Notably, TF motifs with a high genomic clustering tendency are significantly associated with super-enhancers. TF binding profiles showing a high genomic clustering tendency are further enriched at cell-type-specific super-enhancers. TFs with a high binding clustering tendency also possess high liquid-liquid phase separation abilities. Compared to nonclustered TF binding, densely clustered TF binding sites are more enriched at cell-type-specific super-enhancers with higher chromatin accessibility, elevated chromatin interaction and stronger association with cancer outcomes. Our results indicate that the clustered genomic binding patterns and the phase separation properties of TFs collectively contribute to the formation of transcriptional condensates.
许多转录因子（TFs）已被证明可与超级增强子结合，形成转录凝聚物以激活各种细胞系统中的转录。然而，相分离转录凝聚物形成的基因组和表观基因组决定因素仍知之甚少。关于哪些转录因子倾向于与转录凝聚物相关联以及哪些因素影响它们的关联等问题在很大程度上尚未得到解答。在这里，我们系统地分析了人类基因组中的571个DNA序列基序以及不同细胞类型中的6650个转录因子结合谱，以确定有助于形成转录凝聚物的分子特征。我们发现不同转录因子的序列基序在基因组中的分布呈现出明显的聚类趋势。值得注意的是，具有高基因组聚类趋势的转录因子基序与超级增强子显著相关。显示出高基因组聚类趋势的转录因子结合谱在细胞类型特异性超级增强子处进一步富集。具有高结合聚类趋势的转录因子也具有高液-液相分离能力。与非聚类的转录因子结合相比，密集聚类的转录因子结合位点在具有更高染色质可及性、增强的染色质相互作用以及与癌症预后更强关联的细胞类型特异性超级增强子处更为富集。我们的结果表明，转录因子的聚类基因组结合模式和相分离特性共同促成了转录凝聚物的形成。
