{"doi":"10.1073/pnas.2309964120","title":"LST-1 is a bifunctional regulator that feeds back on Notch-dependent transcription to regulate <i>C. elegans</i> germline stem cells","abstract":"Notch signaling regulates stem cells across animal phylogeny. C. elegans Notch signaling activates transcription of two genes, lst-1 and sygl-1 , that encode potent regulators of germline stem cells. The LST-1 protein regulates stem cells in two distinct ways: It promotes self-renewal posttranscriptionally and also restricts self-renewal by a poorly understood mechanism. Its self-renewal promoting activity resides in its N-terminal region, while its self-renewal restricting activity resides in its C-terminal region and requires the Zn finger. Here, we report that LST-1 limits self-renewal by down-regulating Notch-dependent transcription. We detect LST-1 in the nucleus, in addition to its previously known cytoplasmic localization. LST-1 lowers nascent transcript levels at both lst-1 and sygl-1 loci but not at let-858 , a Notch-independent locus. LST-1 also lowers levels of two key components of the Notch activation complex, the LAG-1 DNA binding protein and Notch intracellular domain (NICD). Genetically, an LST-1 Zn finger mutant increases Notch signaling strength in both gain- and loss-of-function GLP-1/Notch receptor mutants. Biochemically, LST-1 co-immunoprecipitates with LAG-1 from nematode extracts, suggesting a direct effect. LST-1 is thus a bifunctional regulator that coordinates posttranscriptional and transcriptional mechanisms in a single protein. This LST-1 bifunctionality relies on its bipartite protein architecture and is bolstered by generation of two LST-1 isoforms, one specialized for Notch downregulation. A conserved theme from worms to human is the coupling of PUF-mediated RNA repression together with Notch feedback in the same protein.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":351711,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":677918,"name":"Tina R. Lynch","orcid":"0000-0003-2730-2669","position":1,"is_corresponding":false},{"id":1096736,"name":"Stephany J. Costa Dos Santos","orcid":"0000-0002-4147-6756","position":2,"is_corresponding":false},{"id":1096737,"name":"Deep H. Kapadia","orcid":"0009-0009-8220-6179","position":3,"is_corresponding":false},{"id":438899,"name":"Sarah L. Crittenden","orcid":null,"position":4,"is_corresponding":false},{"id":438022,"name":"Judith Kimble","orcid":"0000-0001-5622-2073","position":5,"is_corresponding":false},{"id":1096735,"name":"Ahlan Sabah Ferdous","orcid":"0000-0002-3610-304X","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:12:45.897709Z","pmid":"37729202","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":[]}