The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
15
04
2021
accepted:
16
08
2022
pubmed:
7
10
2022
medline:
26
10
2022
entrez:
6
10
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36202974
doi: 10.1038/s41556-022-00996-8
pii: 10.1038/s41556-022-00996-8
pmc: PMC9586874
doi:
Substances chimiques
Hepatocyte Nuclear Factor 1-alpha
0
HNF1A protein, human
0
RNA, Long Noncoding
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1528-1540Subventions
Organisme : Wellcome Trust
ID : WT101033
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L02036X/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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