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KAIST, Duke University Medical Center

Nat. Biotechnol., Published: 19 February 2026 | https://doi.org/10.1038/s41587-026-03013-7 Trimodal single-cell profiling of transcriptome, epigenome and 3D genome in complex tissues with scHiCAR

Xiaolin Wei^1,2,3,12, Yueyuan Xu^1,2,3,12, Dongchan Yang^1,4,12, Kyukwang Kim⁴, Lizhi Yi^1,2,3, Wenzhe Luo^1,2,3, Xin Lin^1,2,3, Yu Xiang^1,2,3, Ashley B. Williams¹, Xiaotao Wang^5,6, Sweta Srivas⁷, Christabel Tan¹, Kan Zhang¹, Wei Li⁸, Yang Eric Li⁹, Feng Yue^5,6, Z. Josh Huang⁷, Inkyung Jung⁴ & Yarui Diao^1,2,3,10,11

¹Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
²Duke Regeneration Center, Duke University Medical Center, Durham, NC, USA.
³Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
⁴Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
⁵Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁶Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁷Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.
⁸Center for Genetic Medicine Research, Center for Cancer and Immunology Research at Children’s National Medical Center, Washington, DC, USA.
⁹Department of Neurosurgery and Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹⁰Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA.
¹¹Department of Pathology, Duke University Medical Center, Durham, NC, USA.
¹²These authors contributed equally: Xiaolin Wei, Yueyuan Xu, Dongchan Yang.

Corresponding authors
Correspondence to Inkyung Jung or Yarui Diao.

Abstract

The three-dimensional (3D) organization of cis-regulatory elements (CREs) is critical in transcription control. However, capturing transcriptome, epigenome and 3D genome from the same single cells remains challenging. Here we present scHiCAR (single-cell Hi-C with assay for transposase-accessible chromatin and RNA sequencing), a plate-based combinatorial barcoding method that simultaneously profiles mRNA, open chromatin and chromosome conformation capture from the same cells. Compared to existing single-cell 3D genome methods, scHiCAR more efficiently enriches long-range cis-interactions anchored at candidate CREs (cCREs). Applied to 1.62 million mouse brain cells and complemented with a deep-learning-based loop caller, scHiCAR accurately defines cell-type-specific transcriptomes, accessible cCREs and 5-kb-resolution enhancer–promoter pairs across 22 brain cell types. scHiCAR also performs robustly in challenging tissues such as skeletal muscle, enabling trimodal single-cell-level analysis of gene regulation dynamics during muscle stem cell regeneration. By providing a scalable and cost-effective system for single-cell trimodal analysis of gene-regulatory landscapes in complex tissues, scHiCAR reveals gene-locus-specific regulatory roles of 3D genome reorganization in transcriptional control.

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