HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2022-10-06
Date Acceptance
2022-08-16
Citation
Nature Cell Biology, 2022, 24, pp.1528-1540
ISSN
1465-7392
Publisher
Nature Research
Start Page
1528
End Page
1540
Journal / Book Title
Nature Cell Biology
Volume
24
Copyright Statement
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Wellcome Trust
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Medical Research Council (MRC)
Identifier
https://www.nature.com/articles/s41556-022-00996-8
Grant Number
101033/C/13/Z
RDC03 79560
RDC03 79560
MR/L02036X/1
MR/L02036X/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
SET ENRICHMENT ANALYSIS
PANCREATIC BETA-CELLS
LONG NONCODING RNAS
INSULIN-SECRETION
DIABETES-MELLITUS
GENE
EXPRESSION
CHROMATIN
PHENOTYPES
REVEALS
Animals
Humans
Mice
Hepatocyte Nuclear Factor 1-alpha
Mammals
Promoter Regions, Genetic
RNA, Long Noncoding
Transcription, Genetic
Animals
Mammals
Humans
Mice
Transcription, Genetic
Hepatocyte Nuclear Factor 1-alpha
Promoter Regions, Genetic
RNA, Long Noncoding
Developmental Biology
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2022-10-06