TY - JOUR T1 - <em>HASTER</em> is a transcriptional stabilizer of <em>HNF1A</em> JF - bioRxiv DO - 10.1101/2021.05.12.443907 SP - 2021.05.12.443907 AU - Anthony Beucher AU - Irene Miguel-Escalada AU - Diego Balboa AU - Matías G. De Vas AU - Miguel Angel Maestro AU - Javier Garcia-Hurtado AU - Aina Bernal AU - Roser Gonzalez-Franco AU - Pierfrancesco Vargiu AU - Holger Heyn AU - Philippe Ravassard AU - Sagrario Ortega AU - Jorge Ferrer Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/13/2021.05.12.443907.abstract N2 - The biological purpose and disease relevance of long noncoding RNAs (lncRNAs) is poorly understood. We examined HASTER, a lncRNA antisense to HNF1A. Haploinsufficient mutations in HNF1A, encoding a homeodomain transcription factor, cause diabetes mellitus. Using mouse and human models, we show that HASTER maintains HNF1A at cell-specific physiological concentrations through positive and negative feedback loops. Haster mutant pancreatic β cells thus showed variegated HNF1A overexpression or silencing, causing insulin-deficiency and diabetes. We demonstrate that the HASTER promoter acts in cis to prevent HNF1A overexpression and silencing, and link HASTER-dependent inhibition to local remodelling of 3D chromatin architecture. We further show that HASTER negative feedback ensures that HNF1A creates open chromatin at appropriate cell-specific genome regions. Our studies expose a cis-regulatory element that is unlike enhancers or silencers, and instead stabilizes expression levels of a pioneer transcription factor. They also show that disruption of a mammalian lncRNA can cause diabetes mellitus.Competing Interest StatementThe authors have declared no competing interest. ER -