Single-cell ultra-high-throughput multiplexed chromatin and RNA profiling reveals gene regulatory dynamics

Enhancers and transcription factors (TFs) are crucial in regulating cellular processes. Current multiomic technologies to study these elements in gene regulatory mechanisms lack multiplexing capability and scalability. Here we present single-cell ultra-high-throughput multiplexed sequencing (SUM-seq) for co-assaying chromatin accessibility and gene expression in single nuclei. SUM-seq enables profiling hundreds of samples at the million cell scale and outperforms current high-throughput single-cell methods. We demonstrate the capability of SUM-seq to (1) resolve temporal gene regulation of macrophage M1 and M2 polarization to bridge TF regulatory networks and immune disease genetic variants, (2) define the regulatory landscape of primary T helper cell subsets and (3) dissect the effect of perturbing lineage TFs via arrayed CRISPR screens in spontaneously differentiating human induced pluripotent stem cells. SUM-seq offers a cost-effective, scalable solution for ultra-high-throughput single-cell multiomic sequencing, accelerating the unraveling of complex gene regulatory networks in cell differentiation, responses to perturbations and disease studies.

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Publication Details

Journal
Nature Methods
Published
2025-05-26
DOI
https://doi.org/10.1038/s41592-025-02700-8
Citations
20
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
16.12
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Single-cell ultra-high-throughput multiplexed chromatin and RNA profiling reveals gene regulatory dynamics

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Single-cell ultra-high-throughput multiplexed chromatin and RNA profiling reveals gene regulatory dynamics

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article en
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Abstract

Enhancers and transcription factors (TFs) are crucial in regulating cellular processes. Current multiomic technologies to study these elements in gene regulatory mechanisms lack multiplexing capability and scalability. Here we present single-cell ultra-high-throughput multiplexed sequencing (SUM-seq) for co-assaying chromatin accessibility and gene expression in single nuclei. SUM-seq enables profiling hundreds of samples at the million cell scale and outperforms current high-throughput single-cell methods. We demonstrate the capability of SUM-seq to (1) resolve temporal gene regulation of macrophage M1 and M2 polarization to bridge TF regulatory networks and immune disease genetic variants, (2) define the regulatory landscape of primary T helper cell subsets and (3) dissect the effect of perturbing lineage TFs via arrayed CRISPR screens in spontaneously differentiating human induced pluripotent stem cells. SUM-seq offers a cost-effective, scalable solution for ultra-high-throughput single-cell multiomic sequencing, accelerating the unraveling of complex gene regulatory networks in cell differentiation, responses to perturbations and disease studies.

Nature MethodsVol. 22(6)
European Molecular Biology Organization (DE), Tampere University of Applied Sciences (FI), Aarhus University (DK), Heidelberg University (DE), University Hospital of Basel (CH), European Molecular Biology Laboratory (ES), Department of Biomedicine Basel (CH), Tampere University (FI), European Molecular Biology Laboratory (DE), European Molecular Biology Laboratory (DE), Erasmus University Rotterdam (NL)
Openalex Percentile: Top 1%
Single-cell and spatial transcriptomics
16.12
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