{"doi":"10.1101/2025.04.03.647067","title":"The Diabetes Gene <i>Tcf7l2</i> Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism","abstract":"Abstract TCF7L2 harbors the strongest genetic association with diabetes identified thus far. However, its function in liver has remained unclear. Here, we find using mice with liver-specific deletion, that Tcf7l2 plays a central role in maintaining hepatic zonation. That is, in the normal liver, many genes show gradients of expression across the liver lobule; in the absence of Tcf7l2 , these gradients collapse. One major consequence is the disorganization of glutamine metabolism, with a loss of the glutamine production program, ectopic expression of the glutamine consumption program, and a decrease in glutamine levels. In parallel, metabolomic profiling shows glutamine to be the most significantly decreased metabolite in individuals harboring the rs7903146 variant in TCF7L2 . Taken together, these data indicate that hepatic TCF7L2 has a secondary role in glycemic control, but a primary role in maintaining transcriptional architecture and glutamine homeostasis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557499,"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":0.9656,"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":602978,"name":"William O’Connor","orcid":null,"position":1,"is_corresponding":false},{"id":1450138,"name":"Pedro Henrique Vendramini","orcid":"0000-0001-9653-7248","position":2,"is_corresponding":false},{"id":1450139,"name":"Mareike Schell","orcid":"0000-0002-9999-445X","position":3,"is_corresponding":false},{"id":845526,"name":"Kiran J. Biddinger","orcid":null,"position":4,"is_corresponding":false},{"id":1450522,"name":"George Pengo","orcid":null,"position":5,"is_corresponding":false},{"id":935337,"name":"Tiffany Fougeray","orcid":null,"position":6,"is_corresponding":false},{"id":31028,"name":"Krishna G. Aragam","orcid":"0000-0003-3223-9131","position":7,"is_corresponding":false},{"id":6945,"name":"Marcia C. Haigis","orcid":"0000-0003-2530-2681","position":8,"is_corresponding":false},{"id":1457379,"name":"Wouter H. Lamers","orcid":"0000-0003-3032-7824","position":9,"is_corresponding":false},{"id":284998,"name":"Linus Tsai","orcid":"0000-0002-0134-6949","position":10,"is_corresponding":false},{"id":44571,"name":"Sudha B. Biddinger","orcid":"0000-0002-2352-067X","position":11,"is_corresponding":false},{"id":430021,"name":"Joanna Krawczyk","orcid":"0000-0001-8263-1890","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T02:55:17.435961Z","pmid":"40291732","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":[]}