Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Genome Biol. 2021 Apr 23;22(1):117. doi: 10.1186/s13059-021-02324-z.
The binding of transcription factors (TF) to genomic targets is critical in the regulation of gene expression. Short, double-stranded DNA sequence motifs are routinely implicated in TF recruitment, but many questions remain on how binding site specificity is governed.
Herein, we reveal a previously unappreciated role for DNA secondary structures as key features for TF recruitment. In a systematic, genome-wide study, we discover that endogenous G-quadruplex secondary structures (G4s) are prevalent TF binding sites in human chromatin. Certain TFs bind G4s with affinities comparable to double-stranded DNA targets. We demonstrate that, in a chromatin context, this binding interaction is competed out with a small molecule. Notably, endogenous G4s are prominent binding sites for a large number of TFs, particularly at promoters of highly expressed genes.
Our results reveal a novel non-canonical mechanism for TF binding whereby G4s operate as common binding hubs for many different TFs to promote increased transcription.
转录因子（TF）与基因组靶标的结合对于基因表达的调控至关重要。短的双链 DNA 序列基序通常与 TF 的招募有关，但关于结合位点特异性如何调控的问题仍然存在。
本文揭示了 DNA 二级结构作为 TF 招募关键特征的先前未被认识到的作用。在一项系统的全基因组研究中，我们发现在人类染色质中，内源性 G-四链体二级结构（G4s）是常见的 TF 结合位点。某些 TF 与 G4s 的结合亲和力可与双链 DNA 靶标相媲美。我们证明，在染色质环境中，这种结合相互作用可被小分子竞争掉。值得注意的是，内源性 G4s 是大量 TF 的突出结合位点，尤其是在高表达基因的启动子处。
我们的结果揭示了一种新的 TF 结合的非经典机制，其中 G4 作为许多不同 TF 的常见结合中心，促进转录的增加。
