HASTER is a transcriptional stabilizer of HNF1A

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 Statement The authors have declared no competing interest.