G-quadruplex structures mark human regulatory chromatin.
G-quadruplex (G4) structural motifs have been linked to transcription, replication and genome instability and are implicated in cancer and other diseases. However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context. Herein we address this through the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5' UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor-induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Robert
R
Hänsel-Hertsch
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Dario
D
Beraldi
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Stefanie V
SV
Lensing
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Giovanni
G
Marsico
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Katherine
K
Zyner
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Aled
0000-0001-5192-3727
A
Parry
Department of Chemistry, University of Cambridge, Cambridge, UK.
Marco
M
Di Antonio
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Jeremy
J
Pike
Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan.
Hiroshi
H
Kimura
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Masashi
M
Narita
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
David
D
Tannahill
Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.|Department of Chemistry, University of Cambridge, Cambridge, UK.|School of Clinical Medicine, University of Cambridge, Cambridge, UK.
Shankar
S
Balasubramanian
D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D054856:G-Quadruplexes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic
D002843:Chromatin