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Nature biotechnology
Oct, 2025;43 (10): 1694-1707.

Droplet Hi-C enables scalable, single-cell profiling of chromatin architecture in heterogeneous tissues.

Lei Chang, Yang Xie, Brett Taylor, Zhaoning Wang, Jiachen Sun, Ethan J Armand, Shreya Mishra, Jie Xu, Melodi Tastemel, Audrey Lie, Zane A Gibbs, Hannah S Indralingam, Tuyet M Tan, Rafael Bejar, Clark C Chen, Frank B Furnari, Ming Hu, Bing Ren
Author Information
  1. Lei Chang: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  2. Yang Xie: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. ORCID
  3. Brett Taylor: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  4. Zhaoning Wang: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. ORCID
  5. Jiachen Sun: Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. ORCID
  6. Ethan J Armand: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  7. Shreya Mishra: Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
  8. Jie Xu: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  9. Melodi Tastemel: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  10. Audrey Lie: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  11. Zane A Gibbs: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  12. Hannah S Indralingam: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  13. Tuyet M Tan: Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
  14. Rafael Bejar: Moores Cancer Center, UC San Diego, La Jolla, CA, USA. ORCID
  15. Clark C Chen: Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA. ORCID
  16. Frank B Furnari: Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  17. Ming Hu: Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. ORCID
  18. Bing Ren: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. biren@health.ucsd.edu. ORCID
PMID: 39424717 DOI: 10.1038/s41587-024-02447-1

Abstract

Current methods for analyzing chromatin architecture are not readily scalable to heterogeneous tissues. Here we introduce Droplet Hi-C, which uses a commercial microfluidic device for high-throughput, single-cell chromatin conformation profiling in droplets. Using Droplet Hi-C, we mapped the chromatin architecture of the mouse cortex and analyzed gene regulatory programs in major cortical cell types. In addition, we used this technique to detect copy number variations, structural variations and extrachromosomal DNA in human glioblastoma, colorectal and blood cancer cells, revealing clonal dynamics and other oncogenic events during treatment. We refined the technique to allow joint profiling of chromatin architecture and transcriptome in single cells, facilitating exploration of the links between chromatin architecture and gene expression in both normal tissues and tumors. Thus, Droplet Hi-C both addresses critical gaps in chromatin analysis of heterogeneous tissues and enhances understanding of gene regulation.

References

Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19431-19439 [PMID: 31506350]
Science. 2018 Aug 31;361(6405):924-928 [PMID: 30166492]
Nat Genet. 2024 Aug;56(8):1701-1711 [PMID: 38744973]
Nat Commun. 2019 Jan 23;10(1):392 [PMID: 30674876]
Cell. 2023 Aug 17;186(17):3674-3685.e14 [PMID: 37494934]
Nature. 2023 Dec;624(7991):366-377 [PMID: 38092913]
Cancer Discov. 2024 Mar 1;14(3):492-507 [PMID: 38197697]
Genome Biol. 2021 Jun 30;22(1):195 [PMID: 34193237]
Nat Rev Cancer. 2019 May;19(5):283-288 [PMID: 30872802]
Nat Biotechnol. 2022 Feb;40(2):254-261 [PMID: 34635838]
Nat Methods. 2023 Sep;20(9):1355-1367 [PMID: 37443338]
Annu Rev Cell Dev Biol. 2021 Oct 6;37:199-232 [PMID: 34228506]
Nat Genet. 2018 Oct;50(10):1388-1398 [PMID: 30202056]
Nat Genet. 2020 Jan;52(1):29-34 [PMID: 31844324]
Genome Biol. 2009;10(3):R25 [PMID: 19261174]
Cell Cycle. 2020 Oct;19(19):2395-2410 [PMID: 32783593]
Cell. 2021 Feb 4;184(3):741-758.e17 [PMID: 33484631]
Genes Dev. 2015 Feb 1;29(3):238-49 [PMID: 25644600]
Cell. 2014 Dec 18;159(7):1665-80 [PMID: 25497547]
Lancet. 1965 Jul 10;1(7402):55-8 [PMID: 14304929]
Nat Commun. 2018 Mar 14;9(1):1069 [PMID: 29540679]
Nature. 2017 Apr 6;544(7648):59-64 [PMID: 28289288]
Nat Commun. 2019 Apr 4;10(1):1538 [PMID: 30948719]
Cell Syst. 2016 Jul;3(1):95-8 [PMID: 27467249]
Bioinformatics. 2022 Jul 11;38(14):3642-3644 [PMID: 35652733]
PLoS Comput Biol. 2024 May 6;20(5):e1012067 [PMID: 38709825]
Genome Biol. 2018 Feb 6;19(1):15 [PMID: 29409532]
Nat Methods. 2019 Oct;16(10):991-993 [PMID: 31384045]
Nat Methods. 2023 Oct;20(10):1493-1505 [PMID: 37640936]
Nat Genet. 2021 Oct;53(10):1469-1479 [PMID: 34594037]
Annu Rev Pathol. 2022 Jan 24;17:367-386 [PMID: 34752712]
Nat Methods. 2019 Dec;16(12):1289-1296 [PMID: 31740819]
Nature. 2022 Dec;612(7940):564-572 [PMID: 36477537]
Nature. 2017 Jul 5;547(7661):61-67 [PMID: 28682332]
Elife. 2022 Dec 07;11: [PMID: 36476408]
Nat Methods. 2021 Jun;18(6):661-668 [PMID: 34092790]
Nature. 2020 Feb;578(7793):82-93 [PMID: 32025007]
Clin Transl Med. 2023 Aug;13(8):e1351 [PMID: 37517066]
Nat Methods. 2019 Oct;16(10):999-1006 [PMID: 31501549]
Nucleic Acids Res. 2021 Jan 8;49(D1):D947-D955 [PMID: 32663312]
Br Med J. 1962 Dec 1;2(5317):1431-5 [PMID: 13978541]
Science. 2014 Jan 3;343(6166):72-6 [PMID: 24310612]
Nat Cell Biol. 2019 Nov;21(11):1393-1402 [PMID: 31685986]
Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):E3114-22 [PMID: 26038577]
Nucleic Acids Res. 2016 Apr 20;44(7):e70 [PMID: 26704975]
N Engl J Med. 2016 Jun 9;374(23):2209-2221 [PMID: 27276561]
Genome Res. 2017 May;27(5):849-864 [PMID: 28396521]
Trends Cancer. 2018 Dec;4(12):810-822 [PMID: 30470303]
Cell. 2018 Apr 5;173(2):530 [PMID: 29625059]
Cell. 2017 Jul 13;170(2):367-381.e20 [PMID: 28709003]
Nature. 2021 Dec;600(7890):731-736 [PMID: 34819668]
PLoS Biol. 2011 Jul;9(7):e1001091 [PMID: 21750661]
Nature. 2017 Apr 6;544(7648):110-114 [PMID: 28355183]
Nature. 2017 Jul 12;547(7662):232-235 [PMID: 28703188]
Cancer Cell. 2021 May 10;39(5):694-707.e7 [PMID: 33836152]
Genome Biol. 2017 Jun 27;18(1):125 [PMID: 28655341]
Mol Cell. 2010 May 28;38(4):576-89 [PMID: 20513432]
Nature. 2021 Oct;598(7879):103-110 [PMID: 34616066]
Cell. 2019 Aug 8;178(4):835-849.e21 [PMID: 31327527]
Trends Genet. 2018 Apr;34(4):270-278 [PMID: 29329720]
Nat Commun. 2022 Nov 11;13(1):6827 [PMID: 36369226]
Nat Genet. 2023 May;55(5):880-890 [PMID: 37142849]
Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14011-14018 [PMID: 31235599]
Science. 2023 Jun 9;380(6649):1070-1076 [PMID: 37289875]
Nature. 2017 Mar 2;543(7643):122-125 [PMID: 28178237]
Sci Rep. 2019 Jun 27;9(1):9354 [PMID: 31249361]
Cell Rep. 2020 Sep 29;32(13):108206 [PMID: 32997998]
Nat Biotechnol. 2010 May;28(5):495-501 [PMID: 20436461]
Nat Rev Clin Oncol. 2022 Nov;19(11):733-743 [PMID: 36131011]
Curr Opin Genet Dev. 2021 Feb;66:78-82 [PMID: 33477016]
Bioinformatics. 2023 Jan 1;39(1): [PMID: 36394265]
Nat Genet. 2020 Sep;52(9):891-897 [PMID: 32807987]
Sci Rep. 2019 Mar 26;9(1):5233 [PMID: 30914743]
Nat Biotechnol. 2025 Oct;43(10):1694-1707 [PMID: 39424717]
Sci Adv. 2022 Jun 17;8(24):eabn9215 [PMID: 35704579]
Cancer Cell. 2020 Aug 10;38(2):263-278.e6 [PMID: 32559496]
Curr Protoc. 2021 Jul;1(7):e198 [PMID: 34286910]
Nature. 2013 Oct 17;502(7471):333-339 [PMID: 24132290]
Nat Methods. 2017 Mar;14(3):263-266 [PMID: 28135255]
Nature. 2013 Oct 3;502(7469):59-64 [PMID: 24067610]
Bioinformatics. 2020 Jan 1;36(1):311-316 [PMID: 31290943]
Nat Struct Mol Biol. 2023 Oct;30(10):1428-1433 [PMID: 37563440]
Nat Rev Mol Cell Biol. 2019 Sep;20(9):535-550 [PMID: 31197269]
Nature. 2021 Oct;598(7879):120-128 [PMID: 34616061]
Nature. 2021 Oct;598(7879):129-136 [PMID: 34616068]
Nature. 2022 Nov;611(7935):387-398 [PMID: 36289338]
Cell Stem Cell. 2014 Jun 5;14(6):762-75 [PMID: 24905166]
PLoS Comput Biol. 2024 May 29;20(5):e1012164 [PMID: 38809952]
Nature. 2019 Nov;575(7784):699-703 [PMID: 31748743]
Development. 2014 Feb;141(3):548-55 [PMID: 24449836]
Nat Methods. 2021 Sep;18(9):1056-1059 [PMID: 34446921]
Nat Biotechnol. 2021 Oct;39(10):1246-1258 [PMID: 34083792]
Nature. 2015 Feb 19;518(7539):331-6 [PMID: 25693564]

Grants

  1. 1UM1HG011585/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
  2. R35HG011922/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
  3. R01 CA258248/NCI NIH HHS
  4. P30 NS047101/NINDS NIH HHS
  5. 5T32GM007198-47/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
  6. 5T32CA067754-27/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
  7. S10 OD026929/NIH HHS
  8. UM1 HG011585/NHGRI NIH HHS
  9. R56 NS080939/NINDS NIH HHS
  10. T32 GM007198/NIGMS NIH HHS
  11. R35 HG011922/NHGRI NIH HHS
  12. T32 CA067754/NCI NIH HHS

MeSH Term

Chromatin
Single-Cell Analysis
Animals
Mice
Humans
Microfluidic Analytical Techniques
DNA Copy Number Variations
Gene Expression Profiling
Cell Line, Tumor

Chemicals

Chromatin
Journal Article

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