Defining genome architecture at base-pair resolution

Peng Hua, Mohsin Badat, Lars L. P. Hanssen, Lance D. Hentges, Nicholas Crump, Damien J. Downes, Danuta M. Jeziorska, A. Marieke Oudelaar, Ron Schwessinger, Stephen Taylor, Thomas A. Milne, Jim R. Hughes, Doug R. Higgs and James O. J. Davies ()
Additional contact information
Peng Hua: University of Oxford
Mohsin Badat: University of Oxford
Lars L. P. Hanssen: University of Oxford
Lance D. Hentges: University of Oxford
Nicholas Crump: University of Oxford
Damien J. Downes: University of Oxford
Danuta M. Jeziorska: University of Oxford
A. Marieke Oudelaar: Max Planck Institute for Biophysical Chemistry
Ron Schwessinger: University of Oxford
Stephen Taylor: University of Oxford
Thomas A. Milne: University of Oxford
Jim R. Hughes: University of Oxford
Doug R. Higgs: University of Oxford
James O. J. Davies: University of Oxford

Nature, 2021, vol. 595, issue 7865, 125-129

Abstract: Abstract In higher eukaryotes, many genes are regulated by enhancers that are 104–106 base pairs (bp) away from the promoter. Enhancers contain transcription-factor-binding sites (which are typically around 7–22 bp), and physical contact between the promoters and enhancers is thought to be required to modulate gene expression. Although chromatin architecture has been mapped extensively at resolutions of 1 kilobase and above; it has not been possible to define physical contacts at the scale of the proteins that determine gene expression. Here we define these interactions in detail using a chromosome conformation capture method (Micro-Capture-C) that enables the physical contacts between different classes of regulatory elements to be determined at base-pair resolution. We find that highly punctate contacts occur between enhancers, promoters and CCCTC-binding factor (CTCF) sites and we show that transcription factors have an important role in the maintenance of the contacts between enhancers and promoters. Our data show that interactions between CTCF sites are increased when active promoters and enhancers are located within the intervening chromatin. This supports a model in which chromatin loop extrusion1 is dependent on cohesin loading at active promoters and enhancers, which explains the formation of tissue-specific chromatin domains without changes in CTCF binding.

Date: 2021
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DOI: 10.1038/s41586-021-03639-4

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