High-resolution targeted 3C interrogation of cis-regulatory element organization at genome-wide scale

Damien J. Downes, Robert A. Beagrie, Matthew E. Gosden, Jelena Telenius, Stephanie J. Carpenter, Lea Nussbaum, Sara Ornellas, Martin Sergeant, Chris Q. Eijsbouts, Ron Schwessinger, Jon Kerry, Nigel Roberts, Arun Shivalingam, Afaf El-Sagheer, A. Marieke Oudelaar, Tom Brown, Veronica J. Buckle, James O. J. Davies and Jim R. Hughes ()
Additional contact information
Damien J. Downes: University of Oxford
Robert A. Beagrie: University of Oxford
Matthew E. Gosden: University of Oxford
Jelena Telenius: University of Oxford
Stephanie J. Carpenter: University of Oxford
Lea Nussbaum: University of Oxford
Sara Ornellas: University of Oxford
Martin Sergeant: University of Oxford
Chris Q. Eijsbouts: Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford
Ron Schwessinger: University of Oxford
Jon Kerry: University of Oxford
Nigel Roberts: University of Oxford
Arun Shivalingam: University of Oxford
Afaf El-Sagheer: University of Oxford
A. Marieke Oudelaar: University of Oxford
Tom Brown: University of Oxford
Veronica J. Buckle: University of Oxford
James O. J. Davies: University of Oxford
Jim R. Hughes: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Chromosome conformation capture (3C) provides an adaptable tool for studying diverse biological questions. Current 3C methods generally provide either low-resolution interaction profiles across the entire genome, or high-resolution interaction profiles at limited numbers of loci. Due to technical limitations, generation of reproducible high-resolution interaction profiles has not been achieved at genome-wide scale. Here, to overcome this barrier, we systematically test each step of 3C and report two improvements over current methods. We show that up to 30% of reporter events generated using the popular in situ 3C method arise from ligations between two individual nuclei, but this noise can be almost entirely eliminated by isolating intact nuclei after ligation. Using Nuclear-Titrated Capture-C, we generate reproducible high-resolution genome-wide 3C interaction profiles by targeting 8055 gene promoters in erythroid cells. By pairing high-resolution 3C interaction calls with nascent gene expression we interrogate the role of promoter hubs and super-enhancers in gene regulation.

Date: 2021
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DOI: 10.1038/s41467-020-20809-6

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