2026-04-29T04:08:51Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/188962024-11-29T20:04:40Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Beucher, Anthony author Miguel-Escalada, Irene author Balboa, Diego author De Vas, Matías G author Maestro, Miguel Angel author Garcia-Hurtado, Javier author Bernal, Aina author Gonzalez-Franco, Roser author Vargiu, Pierfrancesco author Heyn, Holger author Ravassard, Philippe author Ortega, Sagrario author Ferrer, Jorge author 2022-10 The 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. Nat Cell Biol . 2022 ;24(10):1528-1540. http://hdl.handle.net/20.500.12105/18896 36202974 10.1038/s41556-022-00996-8 1476-4679 Nature cell biology The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.