Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Nat Genet. 2024 Oct;56(10):2199-2212. doi: 10.1038/s41588-024-01892-7. Epub 2024 Oct 3.
Many enhancers control gene expression by assembling regulatory factor clusters, also referred to as condensates. This process is vital for facilitating enhancer communication and establishing cellular identity. However, how DNA sequence and transcription factor (TF) binding instruct the formation of high regulatory factor environments remains poorly understood. Here we developed a new approach leveraging enhancer-centric chromatin accessibility quantitative trait loci (caQTLs) to nominate regulatory factor clusters genome-wide. By analyzing TF-binding signatures within the context of caQTLs and comparing episomal versus endogenous enhancer activities, we discovered a class of regulators, 'context-only' TFs, that amplify the activity of cell type-specific caQTL-binding TFs, that is, 'context-initiator' TFs. Similar to super-enhancers, enhancers enriched for context-only TF-binding sites display high coactivator binding and sensitivity to bromodomain-inhibiting molecules. We further show that binding sites for context-only and context-initiator TFs underlie enhancer coordination, providing a mechanistic rationale for how a loose TF syntax confers regulatory specificity.
许多增强子通过组装调节因子簇（也称为凝聚体）来控制基因表达。这个过程对于促进增强子之间的通讯和建立细胞身份至关重要。然而，DNA 序列和转录因子（TF）结合如何指导高调节因子环境的形成仍然知之甚少。在这里，我们开发了一种新的方法，利用以增强子为中心的染色质可及性数量性状基因座（caQTL）在全基因组范围内提名调节因子簇。通过在 caQTL 背景下分析 TF 结合特征，并比较附加体与内源性增强子活性，我们发现了一类被称为“仅背景”TF 的调节剂，它们可以增强细胞类型特异性 caQTL 结合 TF（即“启动子”TF）的活性。与超级增强子类似，富含仅背景 TF 结合位点的增强子显示出高辅激活因子结合和对溴结构域抑制分子的敏感性。我们进一步表明，仅背景和启动子 TF 的结合位点为增强子协调提供了基础，为松散的 TF 语法如何赋予调节特异性提供了机制上的依据。
