Beucher, AnthonyMiguel-Escalada, IreneBalboa, DiegoDe Vas, Matías GMaestro, Miguel AngelGarcia-Hurtado, JavierBernal, AinaGonzalez-Franco, RoserVargiu, PierfrancescoHeyn, HolgerRavassard, PhilippeOrtega, SagrarioFerrer, Jorge2024-03-072024-03-072022-10Nat Cell Biol . 2022 ;24(10):1528-1540.http://hdl.handle.net/20.500.12105/18896The biological purpose of long non-coding RNAs (lncRNAs) is poorly understood. Haploinsufficient mutations in HNF1A homeobox A (HNF1A), encoding a homeodomain transcription factor, cause diabetes mellitus. Here, we examine HASTER, the promoter of an lncRNA antisense to HNF1A. Using mouse and human models, we show that HASTER maintains cell-specific physiological HNF1A concentrations through positive and negative feedback loops. Pancreatic β cells from Haster mutant mice consequently showed variegated HNF1A silencing or overexpression, resulting in hyperglycaemia. HASTER-dependent negative feedback was essential to prevent HNF1A binding to inappropriate genomic regions. We demonstrate that the HASTER promoter DNA, rather than the lncRNA, modulates HNF1A promoter-enhancer interactions in cis and thereby regulates HNF1A transcription. Our studies expose a cis-regulatory element that is unlike classic enhancers or silencers, it stabilizes the transcription of its target gene and ensures the fidelity of a cell-specific transcription factor program. They also show that disruption of a mammalian lncRNA promoter can cause diabetes mellitus.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Hepatocyte Nuclear Factor 1-alphaPromoter Regions, GeneticRNA, Long NoncodingAnimalsHumansMiceMammalsTranscription, GeneticAttribution-NonCommercial-NoDerivatives 4.0 Internacional362029742410152810.1038/s41556-022-00996-81476-4679Nature cell biologyopen access