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

doi:10.1038/s41587-024-02447-1

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

Nat Biotechnol. 2024 Oct 18. doi: 10.1038/s41587-024-02447-1. Online ahead of print.

Authors

Lei Chang^#¹, Yang Xie^#^{1

2}, Brett Taylor^{1

2

3}, Zhaoning Wang¹, Jiachen Sun^{4

5}, Ethan J Armand^{1

6}, Shreya Mishra⁴, Jie Xu¹, Melodi Tastemel¹, Audrey Lie¹, Zane A Gibbs¹, Hannah S Indralingam¹, Tuyet M Tan⁷, Rafael Bejar⁷, Clark C Chen⁸, Frank B Furnari⁹, Ming Hu⁴, Bing Ren^{10

11

12}

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
² Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
³ Medical Scientist Training Program, University of California, San Diego, La Jolla, CA, USA.
⁴ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
⁵ Systems Biology and Bioinformatics PhD Program, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
⁶ Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA.
⁷ Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
⁸ Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA.
⁹ Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
¹⁰ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. biren@health.ucsd.edu.
¹¹ Moores Cancer Center, UC San Diego, La Jolla, CA, USA. biren@health.ucsd.edu.
¹² Center for Epigenomics, Institute for Genomic Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA. biren@health.ucsd.edu.

^# Contributed equally.

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.

Abstract

Grants and funding