RT Journal Article
SR Electronic
T1 HASTER is a transcriptional stabilizer of HNF1A
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.12.443907
DO 10.1101/2021.05.12.443907
A1 Anthony Beucher
A1 Irene Miguel-Escalada
A1 Diego Balboa
A1 Matías G. De Vas
A1 Miguel Angel Maestro
A1 Javier Garcia-Hurtado
A1 Aina Bernal
A1 Roser Gonzalez-Franco
A1 Pierfrancesco Vargiu
A1 Holger Heyn
A1 Philippe Ravassard
A1 Sagrario Ortega
A1 Jorge Ferrer
YR 2021
UL http://biorxiv.org/content/early/2021/05/13/2021.05.12.443907.abstract
AB 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.