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

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• dc.contributor.author Beucher, Anthony
• dc.contributor.author Miguel Escalada, Irene
• dc.contributor.author Balboa, Diego
• dc.contributor.author Vas, Matías G. de
• dc.contributor.author Maestro, Miguel Ángel
• dc.contributor.author Garcia-Hurtado, Javier
• dc.contributor.author Bernal, Aina
• dc.contributor.author González-Franco, Roser
• dc.contributor.author Vargiu, Pierfrancesco
• dc.contributor.author Heyn, Holger
• dc.contributor.author Ravassard, Philippe
• dc.contributor.author Ortega, Sagrario
• dc.contributor.author Ferrer, Jorge
• dc.date.accessioned 2023-01-18T07:35:11Z
• dc.date.available 2023-01-18T07:35:11Z
• dc.date.issued 2022
• dc.description.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.
• dc.description.sponsorship This research was supported by the Medical Research Council (MR/L02036X/1), Wellcome Trust (WT101033), European Research Council (Advanced Grant 789055), Spanish Ministry of Science and Innovation (BFU2014-54284-R and RTI2018-095666-B-I00) and National Institute for Health Research Imperial Biomedical Research Centre. Work in the Centre for Genomic Regulation was supported by the Centres de Recerca de Catalunya programme, Generalitat de Catalunya, Centro de Excelencia Severo Ochoa (CEX2020-001049) and by the Spanish Ministry of Science and Innovation aid to the European Molecular Biology Laboratory partnership. We thank the University of Barcelona School of Medicine animal facility, Center for Genomic Regulation and Imperial College London genomics units, Imperial College High Performance Computing Service, as well as K. Kaestner (University of Pennsylvania), M. Gannon (Vanderbilt University) and D. Tuveson (Cold Spring Harbor Laboratory) for the Cre lines. We thank J. Valcarcel and T. Graf (Center for Genomic Regulation) for comments on the manuscript, F. X. Real (Spanish National Cancer Research Centre) for insights and support, V. Grau and C. Roth for technical support and members of J.F.’s laboratory for valuable discussions.
• dc.format.mimetype application/pdf
• dc.identifier.citation Beucher A, Miguel-Escalada I, Balboa D, De Vas MG, Maestro MA, Garcia-Hurtado J, Bernal A, Gonzalez-Franco R, Vargiu P, Heyn H, Ravassard P, Ortega S, Ferrer J. The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A. Nat Cell Biol. 2022 Oct;24(10):1528-40. DOI: 10.1038/s41556-022-00996-8
• dc.identifier.doi http://dx.doi.org/10.1038/s41556-022-00996-8
• dc.identifier.issn 1465-7392
• dc.identifier.uri http://hdl.handle.net/10230/55325
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Cell Biol. 2022 Oct;24(10):1528-40
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/789055
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-54284-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-095666-B-I00
• dc.rights © 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/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Diabetes
• dc.subject.keyword Gene regulation
• dc.title The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion