G-quadruplex DNA structure is a positive regulator of <i>MYC</i> transcription.

Abstract

DNA structure can regulate genome function. Four-stranded DNA G-quadruplex (G4) structures have been implicated in transcriptional regulation; however, previous studies have not directly addressed the role of an individual G4 within its endogenous cellular context. Using CRISPR to genetically abrogate endogenous G4 structure folding, we directly interrogate the G4 found within the upstream regulatory region of the critical human <i>MYC</i> oncogene. G4 loss leads to suppression of <i>MYC</i> transcription from the P1 promoter that is mediated by the deposition of a de novo nucleosome alongside alterations in RNA polymerase recruitment. We also show that replacement of the endogenous <i>MYC</i> G4 with a different G4 structure from the <i>KRAS</i> oncogene restores G4 folding and <i>MYC</i> transcription. Moreover, we demonstrate that the <i>MYC</i> G4 structure itself, rather than its sequence, recruits transcription factors and histone modifiers. Overall, our work establishes that G4 structures are important features of transcriptional regulation that coordinate recruitment of key chromatin proteins and the transcriptional machinery through interactions with DNA secondary structure, rather than primary sequence.