{"doi":"10.1101/2024.01.29.577779","title":"Rewriting endogenous human transcripts with\n                  <i>trans</i>\n                  -splicing","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  Splicing bridges the gap between static DNA sequence and the diverse and dynamic set of protein products that execute a gene’s biological functions. While exon skipping technologies enable influence over splice site selection, many desired perturbations to the transcriptome require replacement or addition of exogenous exons to target mRNAs: for example, to replace disease-causing exons, repair truncated proteins, or engineer protein fusions. Here, we report the development of\n                  <jats:underline>R</jats:underline>\n                  NA-guid\n                  <jats:underline>e</jats:underline>\n                  d\n                  <jats:italic>trans</jats:italic>\n                  -\n                  <jats:underline>spli</jats:underline>\n                  cing with\n                  <jats:underline>C</jats:underline>\n                  as\n                  <jats:underline>e</jats:underline>\n                  ditor (RESPLICE), inspired by the rare, natural process of trans-splicing that joins exons from two distinct primary transcripts. RESPLICE uses two orthogonal RNA-targeting CRISPR effectors to co-localize a trans-splicing pre-mRNA and to inhibit the cis-splicing reaction, respectively. We demonstrate efficient, specific, and programmable trans-splicing of multi-kilobase RNA cargo into nine endogenous transcripts across two human cell types, achieving up to 45% trans-splicing efficiency in bulk, or 90% when sorting for high effector expression. Our results present RESPLICE as a new mode of RNA editing for fine-tuned and transient control of cellular programs without permanent alterations to the genetic code.\n                </jats:p>","journal":null,"year":null,"id":668521,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":845713,"name":"Cyrus Tau","orcid":"0000-0001-7462-5431","position":1,"is_corresponding":false},{"id":849924,"name":"Matthew Nemeth","orcid":"0009-0001-1224-9116","position":2,"is_corresponding":false},{"id":1025895,"name":"April Pawluk","orcid":"0000-0002-6136-2086","position":3,"is_corresponding":false},{"id":57612,"name":"Silvana Konermann","orcid":"0000-0001-7915-1685","position":4,"is_corresponding":false},{"id":235423,"name":"Patrick D. Hsu","orcid":"0000-0002-9380-2648","position":5,"is_corresponding":false},{"id":554240,"name":"Sita S. Chandrasekaran","orcid":"0000-0002-9604-861X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Rewriting endogenous human transcripts with\n                  <i>trans</i>\n                  -splicing","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  Splicing bridges the gap between static DNA sequence and the diverse and dynamic set of protein products that execute a gene’s biological functions. While exon skipping technologies enable influence over splice site selection, many desired perturbations to the transcriptome require replacement or addition of exogenous exons to target mRNAs: for example, to replace disease-causing exons, repair truncated proteins, or engineer protein fusions. Here, we report the development of\n                  <jats:underline>R</jats:underline>\n                  NA-guid\n                  <jats:underline>e</jats:underline>\n                  d\n                  <jats:italic>trans</jats:italic>\n                  -\n                  <jats:underline>spli</jats:underline>\n                  cing with\n                  <jats:underline>C</jats:underline>\n                  as\n                  <jats:underline>e</jats:underline>\n                  ditor (RESPLICE), inspired by the rare, natural process of trans-splicing that joins exons from two distinct primary transcripts. RESPLICE uses two orthogonal RNA-targeting CRISPR effectors to co-localize a trans-splicing pre-mRNA and to inhibit the cis-splicing reaction, respectively. We demonstrate efficient, specific, and programmable trans-splicing of multi-kilobase RNA cargo into nine endogenous transcripts across two human cell types, achieving up to 45% trans-splicing efficiency in bulk, or 90% when sorting for high effector expression. Our results present RESPLICE as a new mode of RNA editing for fine-tuned and transient control of cellular programs without permanent alterations to the genetic code.\n                </jats:p>","is_dataset_classified":null,"base_score":1.791759469228055,"endowment":1.791759469228055,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19162232","pmcid":null,"openalex_id":"https://openalex.org/W4391396388","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2024,"count":2},{"year":2025,"count":1},{"year":2026,"count":2}],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2024/01/30/2024.01.29.577779.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2024/01/30/2024.01.29.577779.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2024.01.29.577779","host_type":"publisher"},{"url":"http://dx.doi.org/10.1101/2024.01.29.577779","host_type":"repository"}],"fields_of_study":["RNA Research and Splicing","CRISPR and Genetic Engineering","RNA regulation and disease"],"mesh_terms":[],"keywords":["Exon","RNA splicing","Alternative splicing","Biology","Exon skipping","Intron","Exonic splicing enhancer","RNA","Minigene","Genetics","Gene","Computational biology"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-14T11:49:52.639885Z","pmid":null,"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":[]}