Imperial College London
Alternate

ProfessorJorgeFerrer

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Medicine and Genetics
 
 
 
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Contact

 

+44 (0)20 7594 0968j.ferrer

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Beucher:2022:10.1038/s41556-022-00996-8,
author = {Beucher, A and Miguel, Escalada I and Balboa, D and De, Vas M and Maestro, MA and Garcia-Hurtado, J and Bernal, A and Gonzalez, Franco R and Vargiu, P and Heyn, H and Ravassard, P and Ortega, S and Ferrer, J},
doi = {10.1038/s41556-022-00996-8},
journal = {Nature Cell Biology},
pages = {1528--1540},
title = {HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A},
url = {http://dx.doi.org/10.1038/s41556-022-00996-8},
volume = {24},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Beucher,A
AU  - Miguel,Escalada I
AU  - Balboa,D
AU  - De,Vas M
AU  - Maestro,MA
AU  - Garcia-Hurtado,J
AU  - Bernal,A
AU  - Gonzalez,Franco R
AU  - Vargiu,P
AU  - Heyn,H
AU  - Ravassard,P
AU  - Ortega,S
AU  - Ferrer,J
DO  - 10.1038/s41556-022-00996-8
EP  - 1540
PY  - 2022///
SN  - 1465-7392
SP  - 1528
TI  - HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A
T2  - Nature Cell Biology
UR  - http://dx.doi.org/10.1038/s41556-022-00996-8
UR  - https://www.nature.com/articles/s41556-022-00996-8
UR  - http://hdl.handle.net/10044/1/99697
VL  - 24
ER  -
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