{"doi":"10.1126/sciadv.adt1532","title":"Programmable multistep CRISPR gene activation via control of RNA polymerase III termination","abstract":"Although genomes encode instructions for mammalian cell differentiation with rich syntactic relationships, existing methods for genetically programming cells have only modest capabilities for stepwise gene regulation. Here, we develop a sequential genetic system that transcriptionally activates endogenous genes in a preprogrammed, stepwise manner. This system uses the removal of an RNA polymerase III termination sequence to trigger both the transcriptional activation and DNA endonuclease activities of a Cas9-VPR protein, driving progression through a cascade of gene activation events. The system's functionality in human cells, including iPSCs, enables the development of a path for cellular programming by controlling the sequential order of gene activation to influence cellular states.","journal":"Science Advances","year":2025,"id":549245,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"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":1443445,"name":"Andrew C. Nielsen","orcid":"0009-0004-5574-1866","position":1,"is_corresponding":false},{"id":423137,"name":"Maureen Regan","orcid":null,"position":2,"is_corresponding":false},{"id":266599,"name":"Georgina Mancinelli","orcid":"0000-0002-5216-7086","position":3,"is_corresponding":false},{"id":1443962,"name":"Renee F. De Pooter","orcid":null,"position":4,"is_corresponding":false},{"id":563505,"name":"Stephen Arnovitz","orcid":"0000-0001-5307-8694","position":5,"is_corresponding":false},{"id":1443446,"name":"Caspian Harding","orcid":"0009-0007-2836-565X","position":6,"is_corresponding":false},{"id":1443447,"name":"Michaele McGregor","orcid":"0009-0004-6856-8476","position":7,"is_corresponding":false},{"id":498550,"name":"Nikolas G. Balanis","orcid":null,"position":8,"is_corresponding":false},{"id":422162,"name":"Ryan Clarke","orcid":"0000-0002-3814-5585","position":9,"is_corresponding":false},{"id":331011,"name":"Bradley J. Merrill","orcid":"0000-0001-5074-3345","position":10,"is_corresponding":false},{"id":1135969,"name":"Anupama K. Puppala","orcid":"0000-0002-9701-7129","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:54:07.823422Z","pmid":"41348871","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":[]}