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Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture

Abstract

Chromosome conformation capture (3C) methods measure the spatial proximity between DNA elements in the cell nucleus. Many methods have been developed to sample 3C material, including the Capture-C family of protocols. Capture-C methods use oligonucleotides to enrich for interactions of interest from sequencing-ready 3C libraries. This approach is modular and has been adapted and optimized to work for sampling of disperse DNA elements (NuTi Capture-C), including from low cell inputs (LI Capture-C), as well as to generate Hi-C like maps for specific regions of interest (Tiled-C) and to interrogate multiway interactions (Tri-C). We present the design, experimental protocol and analysis pipeline for NuTi Capture-C in addition to the variations for generation of LI Capture-C, Tiled-C and Tri-C data. The entire procedure can be performed in 3 weeks and requires standard molecular biology skills and equipment, access to a next-generation sequencing platform, and basic bioinformatic skills. Implemented with other sequencing technologies, these methods can be used to identify regulatory interactions and to compare the structural organization of the genome in different cell types and genetic models.

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Fig. 1: Capture-C is modular and adaptable for characterizing chromatin folding.
Fig. 2: Capture-C design considerations.
Fig. 3: Quality control of 3C libraries.
Fig. 4: Adaptations for high-specificity sequencing.
Fig. 5: Anticipated results.

Data availability

Example results were generated by analyzing GSE129378 (ref. 10).

Code availability

CapCruncher can be used following direct installation from Bioconda or accessed via GitHub91 (https://github.com/sims-lab/CapCruncher/releases).

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Acknowledgements

We thank all of our collaborators who provided feedback and sought guidance when using this protocol. These methods were developed as part of the Wellcome Investigation of Genome Wide Association Mechanisms (WIGWAM) Consortium funded by a Wellcome Strategic Award (106130/Z/14/Z). J.R.H. received Medical Research Council (MRC) Core Funding (MC_UU_00016/14). T.A.M. and A.L.S. are supported by Molecular Haematology Unit grant MC_UU_00016/6. J.O.J.D. was supported by grants from Wellcome (098931/Z/12/Z) and the MRC (MR/R008108/1). D.S. received Wellcome funding (204826/Z/16/Z). A.M.O. is supported by the Max Planck Society. M.A.K. and T.V. are supported by the International Max Planck Research School for Genome Science, part of the Göttingen Graduate Center for Neurosciences, Biophysics and Molecular Biosciences.

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Authors and Affiliations

Authors

Contributions

J.O.J.D. and J.R.H. designed the original protocol. D.J.D., M.A.K., T.V. and A.M.O. performed optimization experiments and developed the protocol. D.J.D., A.L.S., J.O.J.D., K.R., D.S. and A.M.O. designed and created the data analysis scripts. D.S., T.A.M., A.M.O. and J.R.H. acquired funding and oversaw the work. D.J.D. and A.M.O. wrote the manuscript and generated the figures. All authors critically evaluated and edited the manuscript.

Corresponding authors

Correspondence to A. Marieke Oudelaar or Jim R. Hughes.

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Competing interests

J.R.H. and J.O.J.D. are founders and shareholders of Nucleome Therapeutics. J.R.H., J.O.J.D. and D.J.D. are paid consultants for Nucleome Therapeutics. J.R.H. and J.O.J.D. hold patents for Capture-C (WO2017068379A1, EP3365464B1, US10934578B2) and have a patent application for MCC. T.A.M. is a founding shareholder of OxStem Oncology (a subsidiary company of OxStem Ltd.) and a founding shareholder and paid consultant for Sandymount Therapeutics (a subsidiary company of Dark Blue Therapeutics). The other authors have no competing interests.

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Nature Protocols thanks Zhijun Duan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Key references using this protocol

Downes, D. J. et al. Nat. Commun. 12, 531 (2021): https://doi.org/10.1038/s41467-020-20809-6

Oudelaar, A. M. et al. Nat. Commun. 11, 2722 (2020): https://doi.org/10.1038/s41467-020-16598-7

Oudelaar, A. M. et al. Nat. Genet. 50, 1744–1751 (2018): https://doi.org/10.1038/s41588-018-0253-2

Supplementary information

Supplementary Information

Supplementary Manual

Supplementary Data 1

Files for designing NuTi Capture-C viewpoints, analyzing NuTi Capture-C viewpoints and running CapCruncher.

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Downes, D.J., Smith, A.L., Karpinska, M.A. et al. Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture. Nat Protoc 17, 445–475 (2022). https://doi.org/10.1038/s41596-021-00651-w

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