The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A

Beucher, Anthony; Miguel Escalada, Irene; Balboa, Diego; Vas, Matías G. de; Maestro, Miguel Ángel; Garcia-Hurtado, Javier; Bernal, Aina; González-Franco, Roser; Vargiu, Pierfrancesco; Heyn, Holger; Ravassard, Philippe; Ortega, Sagrario; Ferrer, Jorge

doi:http://dx.doi.org/10.1038/s41556-022-00996-8

The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A

License

Citation

Beucher A, Miguel-Escalada I, Balboa D, De Vas MG, Maestro MA, Garcia-Hurtado J, Bernal A, Gonzalez-Franco R, Vargiu P, Heyn H, Ravassard P, Ortega S, Ferrer J. The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A. Nat Cell Biol. 2022 Oct;24(10):1528-40. DOI: 10.1038/s41556-022-00996-8

Abstract

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.