Decoding heterogeneous single-cell perturbation responses
Understanding how cells respond differently to perturbation is crucial in cell biology, but existing methods often fail to accurately quantify and interpret heterogeneous single-cell responses. Here we introduce the perturbation-response score (PS), a method to quantify diverse perturbation responses at a single-cell level. Applied to single-cell perturbation datasets such as Perturb-seq, PS outperforms existing methods in quantifying partial gene perturbations. PS further enables single-cell dosage analysis without needing to titrate perturbations, and identifies 'buffered' and 'sensitive' response patterns of essential genes, depending on whether their moderate perturbations lead to strong downstream effects. PS reveals differential cellular responses on perturbing key genes in contexts such as T cell stimulation, latent HIV-1 expression and pancreatic differentiation. Notably, we identified a previously unknown role for the coiled-coil domain containing 6 (CCDC6) in regulating liver and pancreatic cell fate decisions. PS provides a powerful method for dose-to-function analysis, offering deeper insights from single-cell perturbation data.
Authors
- Dapeng Yang (ORCID: https://orcid.org/0000-0001-8687-4486)
- Breanna Williams (ORCID: https://orcid.org/0000-0003-0656-1872)
- Natalie F. McMyn (ORCID: https://orcid.org/0000-0001-6125-3480)
- Dongyuan Song (ORCID: https://orcid.org/0000-0003-1114-1215)
- Weiwei Dai (ORCID: https://orcid.org/0000-0002-9215-065X)
- Janet D. Siliciano (ORCID: https://orcid.org/0000-0001-6712-3775)
- Qingyang Wang (ORCID: https://orcid.org/0000-0002-1051-609X)
- Tilmann Bürckstümmer (ORCID: https://orcid.org/0000-0001-5681-8045)
- Anatoly N. Vasilyev (ORCID: https://orcid.org/0000-0002-1573-0730)
- Yarui Diao (ORCID: https://orcid.org/0000-0001-5842-4082)
- Anke Loregger
- Jingyi Jessica Li (ORCID: https://orcid.org/0000-0002-9288-5648)
- Danwei Huangfu (ORCID: https://orcid.org/0000-0002-1145-6199)
- Nicole Untermoser
- Adam Krejčí
- Bicna Song (ORCID: https://orcid.org/0000-0001-6701-777X)
- Robert F. Siliciano (ORCID: https://orcid.org/0000-0002-1764-1993)
- Lumen Chao (ORCID: https://orcid.org/0000-0002-9057-6585)
- Hanuman T. Kale
- Wei Li (ORCID: https://orcid.org/0000-0002-2163-7903)
- Hao Zhang (ORCID: https://orcid.org/0000-0002-1304-5895)
- Dingyu Liu (ORCID: https://orcid.org/0009-0006-5870-6374)
- Xiaolong Cheng (ORCID: https://orcid.org/0000-0001-9513-6258)
- Bess P. Rosen (ORCID: https://orcid.org/0000-0003-1167-656X)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Children's National (US)
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- University of California, Los Angeles (US)
- George Washington University (US)
- Cornell University (US)
- Johns Hopkins Medicine (US)
- Kettering University (US)
- Duke Medical Center (US)
- Duke University Hospital (US)
- Weill Cornell Medicine (US)
- UConn Health (US)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1038/s41556-025-01626-9
- Citations
- 19
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 15.31