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Pooled CRISPR screens with joint single-nucleus chromatin accessibility and transcriptome profiling

Nature Biotechnology volume 43, pages 1628–1634 (2025)Cite this article

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Abstract

Pooled single-cell CRISPR screens have profiled either gene expression or chromatin accessibility but not both modalities. Here we develop MultiPerturb-seq, a high-throughput CRISPR screening platform with joint single-nucleus chromatin accessibility, transcriptome and guide RNA capture using combinatorial indexing combined with droplet microfluidics to scale throughput and integrate all three modalities. We identify key differentiation genes in a rare pediatric cancer and establish ZNHIT1 as a potential target for cancer reprogramming therapy.

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Fig. 1: MultiPerturb-seq combines single-cell RNA-seq and single-cell ATAC-seq with pooled CRISPR perturbations for high-throughput functional genomics.
Fig. 2: MultiPerturb-seq identifies genetic perturbations that trigger differentiation in AT/RT.
Fig. 3: ZNHIT1 loss drives AT/RT cell-cycle arrest and differentiation through decreased H2A.Z deposition.

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Data availability

MultiPerturb-seq data can be downloaded from BioProject (accession number PRJNA1160410). The human genome hg38 (GRCh38.p14) was from the University of California, Santa Cruz Genome Browser (https://hgdownload.soe.ucsc.edu/goldenPath/hg38/bigZips/hg38.fa.gz). The joint human (hg38, GENCODE v32/Ensembl98) and mouse (mm10, GENCODE vM23/Ensembl98) genome (2020-A) was from 10x Genomics (https://cf.10xgenomics.com/supp/cell-exp/refdata-gex-GRCh38-and-mm10-2020-A.tar.gz). Reference developmental and adult atlases were downloaded from https://apps.kaessmannlab.org/evodevoapp/ (ref. 29), https://descartes.brotmanbaty.org/ (ref. 35) and http://catlas.org/humanbrain/ (ref. 36). Data from previously published studies were from the Sequence Read Archive or Gene Expression Omnibus: CRISPR-sciATAC6 (PRJNA674902), scifiRNA-seq11 (PRJNA713314), sci-CAR-seq16 (PRJNA481032), SNARE-seq17 (PRJNA520914), Paired-seq18 (PRJNA539985) and SHARE-seq15 (PRJNA588784).

Code availability

Code for data processing and visualization is available from GitLab (https://gitlab.com/sanjanalab/mps).

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Acknowledgements

We thank the entire Sanjana laboratory for their support and advice. We also thank P. Smibert, C. Zhu and S. Hao for sharing their single-cell expertise, X. Chen and S. Teichman for single-cell schematics and the NYU Biology Genomics Core for sequencing resources. A.C. is supported by the Swedish Research Council. Z.Z.G. is supported by the National Institutes of Health (NIH) T32 training grant (grant no. GM136573). E.K. is partially supported by the National Science Foundation (NSF) (DMS-2113072 and DMS-2310654). N.D. is supported by the NIH–Office of the Director (R03OD034499). N.D. and J.P.G. are supported by the Ty Louis Campbell Foundation. N.E.S. is supported by the NIH–National Human Genome Research Institute (DP2HG010099 and R01HG012790), NIH–National Cancer Institute (R01CA218668 and R01CA279135), NIH–National Institute of Allergy and Infectious Diseases (R01AI176601), NIH–National Heart, Lung, and Blood Institute (R01HL168247), the Simons Foundation for Autism Research (Genomics of ASD 896724), the MacMillan Center for the Study of the Non-coding Cancer Genome and New York University and New York Genome Center funds.

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Authors and Affiliations

  1. New York Genome Center, New York, NY, USA

    Rachel E. Yan, Alba Corman, Lyla Katgara, Xiao Wang, Xinhe Xue, Zoran Z. Gajic, Richard Sam, Michael Farid, Samuel M. Friedman, Jungwook Choo, Ivan Raimondi & Neville E. Sanjana

  2. Department of Biology, New York University, New York, NY, USA

    Rachel E. Yan, Alba Corman, Lyla Katgara, Xiao Wang, Xinhe Xue, Zoran Z. Gajic, Richard Sam, Michael Farid, Samuel M. Friedman, Jungwook Choo & Neville E. Sanjana

  3. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Rachel E. Yan & Shridar Ganesan

  4. Department of Neurological Surgery, Weill Cornell Medicine, New York, NY, USA

    Rachel E. Yan, Jeffrey P. Greenfield & Nadia Dahmane

  5. Department of Statistics and Data Science, University of Pennsylvania, Philadelphia, PA, USA

    Eugene Katsevich

  6. Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

    Ivan Raimondi

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  1. Rachel E. Yan
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Contributions

R.E.Y. and N.E.S. designed the study. R.E.Y., N.D. and N.E.S. designed the CRISPR library. R.E.Y. performed MultiPerturb-seq experiments and led the analysis. X.X. and A.C. assisted with the pooled screen. N.E.S., E.K., I.R., Z.Z.G., X.W., M.F. and S.F. performed additional data analysis. R.E.Y., L.K., X.W., R.S., X.X., J.C. and A.C. performed arrayed validation. S.G., N.D., J.P.G. and N.E.S. supervised the study. R.E.Y. and N.E.S. wrote the paper with input from all authors.

Corresponding author

Correspondence to Neville E. Sanjana.

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Competing interests

The New York Genome Center and New York University have applied for patents related to the work in this article. N.E.S. is an adviser to Qiagen and a cofounder and adviser of TruEdit Bio and OverT Bio. The other authors declare no competing interests.

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Yan, R.E., Corman, A., Katgara, L. et al. Pooled CRISPR screens with joint single-nucleus chromatin accessibility and transcriptome profiling. Nat Biotechnol 43, 1628–1634 (2025). https://doi.org/10.1038/s41587-024-02475-x

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