Multiome Perturb-seq unlocks scalable discovery of integrated perturbation effects on the transcriptome and epigenome Journal Article
| Authors: | Metzner, E.; Southard, K. M.; Norman, T. M. |
| Article Title: | Multiome Perturb-seq unlocks scalable discovery of integrated perturbation effects on the transcriptome and epigenome |
| Abstract: | Single-cell CRISPR screens link genetic perturbations to transcriptional states, but high-throughput methods connecting these induced changes to their regulatory foundations are limited. Here, we introduce Multiome Perturb-seq, extending single-cell CRISPR screens to simultaneously measure perturbation-induced changes in gene expression and chromatin accessibility. We apply Multiome Perturb-seq in a CRISPRi screen of 13 chromatin remodelers in human RPE-1 cells, achieving efficient assignment of sgRNA identities to single nuclei via an improved method for capturing barcode transcripts from nuclear RNA. We organize expression and accessibility measurements into coherent programs describing the integrated effects of perturbations on cell state, finding that ARID1A and SUZ12 knockdowns induce programs enriched for developmental features. Modeling of perturbation-induced heterogeneity connects accessibility changes to changes in gene expression, highlighting the value of multimodal profiling. Overall, our method provides a scalable and simply implemented system to dissect the regulatory logic underpinning cell state. A record of this paper's transparent peer review process is included in the supplemental information. © 2024 The Author(s) |
| Keywords: | controlled study; dna binding protein; human cell; genetics; dna-binding proteins; metabolism; gene; gene expression; gene expression profiling; neoplasm proteins; cell line; transcription factor; transcription factors; rna; regulatory mechanism; chromatin; tumor protein; gene control; gene regulatory network; cell nucleus; gene silencing; genetic screening; transcriptome; functional genomics; rna transcription; chromatin assembly and disassembly; expression vector; gene regulatory networks; single cell analysis; single-cell analysis; procedures; nuclear rna; epigenome; polycomb repressive complex 2; chromatin accessibility; arid1a gene; suz12 protein, human; gene knockdown; humans; human; article; differential gene expression; clustered regularly interspaced short palindromic repeat; crispr cas system; crispr-cas systems; arid1a protein, human; single cell rna seq; single-cell genomics; high throughput technology; perturb-seq; crispri; multiome; htert-rpe1 cell line; multiome perturb seq; suz12 gene |
| Journal Title: | Cell Systems |
| Volume: | 16 |
| Issue: | 1 |
| ISSN: | 2405-4712 |
| Publisher: | Cell Press |
| Date Published: | 2025-01-15 |
| Start Page: | 101161 |
| Language: | English |
| DOI: | 10.1016/j.cels.2024.12.002 |
| PUBMED: | 39689711 |
| PROVIDER: | scopus |
| PMCID: | PMC11738662 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Thomas M. Norman -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work