G-quadruplexes are transcription factor binding hubs in human chromatin

Jochen Spiegel,Robert Hänsel-Hertsch,Shankar Balasubramanian,Sergio Martínez Cuesta,Santosh Adhikari,David Tannahill

doi:10.1186/s13059-021-02324-z

Abstract

BackgroundThe 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.ResultsHerein, 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.ConclusionsOur 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.

Highlights

Transcription factors (TFs) control gene expression and chromatin structure through precise protein-DNA interactions at specific genome locations [1]
TF binding is tightly linked to endogenous G4 structures in the human genome As DNA structure is fundamental to DNA-protein interactions, we explored the relationship of endogenous TF binding and G4 secondary structures
We compared endogenous G4s to the binding sites of various chromatin-associated proteins and histone marks derived from ENCODE

Summary

Introduction

Transcription factors (TFs) control gene expression and chromatin structure through precise protein-DNA interactions at specific genome locations [1]. Preferred binding sites for hundreds of TFs exhibit short, defined DNA recognition motifs, commonly called “consensus sequences,” based on in vitro binding studies [2,3,4] and in chromatin using ChIP-seq [5]. Two modes of protein-DNA recognition are described to contribute to TF binding specificity [6]. The second mode uses shape readout and is mediated by local structural features of the DNA double helix, such as minor groove width, base roll, and helix twist [8,9,10]. Double-stranded DNA sequence motifs are routinely implicated in TF recruitment, but many questions remain on how binding site specificity is governed

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Conclusion