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A single-cell method to map higher-order 3D genome organization in thousands of individual cells reveals structural heterogeneity in mouse ES cells

View ORCID ProfileMary V. Arrastia, View ORCID ProfileJoanna W. Jachowicz, View ORCID ProfileNoah Ollikainen, View ORCID ProfileMatthew S. Curtis, Charlotte Lai, View ORCID ProfileSofia A. Quinodoz, David A. Selck, Mitchell Guttman, View ORCID ProfileRustem F. Ismagilov
doi: https://doi.org/10.1101/2020.08.11.242081
Mary V. Arrastia
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
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  • ORCID record for Mary V. Arrastia
Joanna W. Jachowicz
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
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  • ORCID record for Joanna W. Jachowicz
Noah Ollikainen
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
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Matthew S. Curtis
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
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Charlotte Lai
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
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Sofia A. Quinodoz
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
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  • ORCID record for Sofia A. Quinodoz
David A. Selck
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
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Mitchell Guttman
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
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  • For correspondence: mguttman@caltech.edu rustem.admin@caltech.edu
Rustem F. Ismagilov
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
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  • ORCID record for Rustem F. Ismagilov
  • For correspondence: mguttman@caltech.edu rustem.admin@caltech.edu
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ABSTRACT

In eukaryotes, the nucleus is organized into a three dimensional structure consisting of both local interactions such as those between enhancers and promoters, and long-range higher-order structures such as nuclear bodies. This organization is central to many aspects of nuclear function, including DNA replication, transcription, and cell cycle progression. Nuclear structure intrinsically occurs within single cells; however, measuring such a broad spectrum of 3D DNA interactions on a genome-wide scale and at the single cell level has been a great challenge. To address this, we developed single-cell split-pool recognition of interactions by tag extension (scSPRITE), a new method that enables measurements of genome-wide maps of 3D DNA structure in thousands of individual nuclei. scSPRITE maximizes the number of DNA contacts detected per cell enabling high-resolution genome structure maps within each cells and is easy-to-use and cost-effective. scSPRITE accurately detects chromosome territories, active and inactive compartments, topologically associating domains (TADs), and higher-order structures within single cells. In addition, scSPRITE measures cell-to-cell heterogeneity in genome structure at different levels of resolution and shows that TADs are dynamic units of genome organization that can vary between different cells within a population. scSPRITE will improve our understanding of nuclear architecture and its relationship to nuclear function within an individual nucleus from complex cell types and tissues containing a diverse population of cells.

Competing Interest Statement

This paper is the subject of a patent application filed by Caltech. R.F.I. has a financial interest in Talis Biomedical Corp.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154353

  • https://github.com/caltech-bioinformatics-resource-center/Guttman_Ismagilov_Labs

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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A single-cell method to map higher-order 3D genome organization in thousands of individual cells reveals structural heterogeneity in mouse ES cells
Mary V. Arrastia, Joanna W. Jachowicz, Noah Ollikainen, Matthew S. Curtis, Charlotte Lai, Sofia A. Quinodoz, David A. Selck, Mitchell Guttman, Rustem F. Ismagilov
bioRxiv 2020.08.11.242081; doi: https://doi.org/10.1101/2020.08.11.242081
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A single-cell method to map higher-order 3D genome organization in thousands of individual cells reveals structural heterogeneity in mouse ES cells
Mary V. Arrastia, Joanna W. Jachowicz, Noah Ollikainen, Matthew S. Curtis, Charlotte Lai, Sofia A. Quinodoz, David A. Selck, Mitchell Guttman, Rustem F. Ismagilov
bioRxiv 2020.08.11.242081; doi: https://doi.org/10.1101/2020.08.11.242081

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