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

• Published in: Nature cell biology Vol. 24; no. 10; pp. 1528 - 1540
• Main Authors: Beucher, Anthony, Miguel-Escalada, Irene, Balboa, Diego, De Vas, Matías G., Maestro, Miguel Angel, Garcia-Hurtado, Javier, Bernal, Aina, Gonzalez-Franco, Roser, Vargiu, Pierfrancesco, Heyn, Holger, Ravassard, Philippe, Ortega, Sagrario, Ferrer, Jorge
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2022; Nature Publishing Group
• Subjects: 631/208/200; 692/163/2743/137; Animal models; Animals; Beta cells; Biomedical and Life Sciences; Cancer Research; Cell Biology; Developmental Biology; Diabetes; Diabetes mellitus; Enhancers; Feedback; Feedback loops; Hepatocyte Nuclear Factor 1-alpha - genetics; Homeobox; Humans; Hyperglycemia; Life Sciences; Mammals; Mice; Mutation; Negative feedback; Non-coding RNA; Promoter Regions, Genetic; RNA, Long Noncoding - genetics; Stem Cells; Transcription factors; Transcription, Genetic - genetics; Transcription, Genetic - physiology
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-022-00996-8

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.
Beucher et al. show that the promoter of lncRNA
HASTER
is a
cis
-regulatory feedback element that stabilizes HNF1A concentrations.