{"doi":"10.1016/j.cell.2025.02.012","title":"Simultaneous CRISPR screening and spatial transcriptomics reveal intracellular, intercellular, and functional transcriptional circuits","abstract":"Pooled optical screens have enabled the study of cellular interactions, morphology, or dynamics at massive scale, but they have not yet leveraged the power of highly plexed single-cell resolved transcriptomic readouts to inform molecular pathways. Here, we present a combination of imaging spatial transcriptomics with parallel optical detection of in situ amplified guide RNAs (Perturb-FISH). Perturb-FISH recovers intracellular effects that are consistent with single-cell RNA-sequencing-based readouts of perturbation effects (Perturb-seq) in a screen of lipopolysaccharide response in cultured monocytes, and it uncovers intercellular and density-dependent regulation of the innate immune response. Similarly, in three-dimensional xenograft models, Perturb-FISH identifies tumor-immune interactions altered by genetic knockout. When paired with a functional readout in a separate screen of autism spectrum disorder risk genes in human-induced pluripotent stem cell (hIPSC) astrocytes, Perturb-FISH shows common calcium activity phenotypes and their associated genetic interactions and dysregulated molecular pathways. Perturb-FISH is thus a general method for studying the genetic and molecular associations of spatial and functional biology at single-cell resolution.","journal":"Cell","year":2025,"id":508801,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":93,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9485,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":621162,"name":"Aiping Jiang","orcid":"0000-0002-8389-2950","position":1,"is_corresponding":false},{"id":1160923,"name":"Serwah Danquah","orcid":null,"position":2,"is_corresponding":false},{"id":815151,"name":"Vera Valakh","orcid":"0000-0001-7149-1562","position":3,"is_corresponding":false},{"id":6107,"name":"Brooke Simonton","orcid":"0000-0002-1366-1268","position":4,"is_corresponding":false},{"id":6106,"name":"Jon Bezney","orcid":"0000-0003-2233-4792","position":5,"is_corresponding":false},{"id":16001,"name":"Robert T. Manguso","orcid":"0000-0003-1336-413X","position":6,"is_corresponding":false},{"id":36448,"name":"Kathleen B. Yates","orcid":"0000-0002-7383-5573","position":7,"is_corresponding":false},{"id":74333,"name":"Ralda Nehme","orcid":"0000-0001-7215-3311","position":8,"is_corresponding":false},{"id":6114,"name":"Brian Cleary","orcid":"0000-0003-0825-7129","position":9,"is_corresponding":false},{"id":43402,"name":"Samouil L. Farhi","orcid":"0000-0003-1359-4568","position":10,"is_corresponding":false},{"id":6115,"name":"Loïc Binan","orcid":"0000-0002-3886-5873","position":0,"is_corresponding":true}],"reference_count":108,"raw_metadata":null,"created_at":"2026-07-19T02:47:00.188082Z","pmid":"40081369","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}