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

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 m...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/55325
Acceso en línea:http://hdl.handle.net/10230/55325
http://dx.doi.org/10.1038/s41556-022-00996-8
Access Level:acceso abierto
Palabra clave:Diabetes
Gene regulation
Descripción
Sumario: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.

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