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

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 m...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18896
Acceso en línea:http://hdl.handle.net/20.500.12105/18896
Access Level:acceso abierto
Palabra clave:Hepatocyte Nuclear Factor 1-alpha
Promoter Regions, Genetic
RNA, Long Noncoding
Animals
Humans
Mice
Mammals
Transcription, Genetic
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spelling The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.Beucher, AnthonyMiguel-Escalada, IreneBalboa, DiegoDe Vas, Matías GMaestro, Miguel AngelGarcia-Hurtado, JavierBernal, AinaGonzalez-Franco, RoserVargiu, PierfrancescoHeyn, HolgerRavassard, PhilippeOrtega, SagrarioFerrer, JorgeHepatocyte Nuclear Factor 1-alphaPromoter Regions, GeneticRNA, Long NoncodingAnimalsHumansMiceMammalsTranscription, GeneticThe 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.Nature Publishing GroupUK Research and InnovationWellcome TrustUnión Europea. Comisión Europea. European Research Council (ERC)Ministerio de Ciencia y Universidades (España)NIHR - Imperial Biomedical Research Centre (Reino Unido)Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Centres de Recerca de Catalunya (CERCA)20242024-03-0720222022-10-0120222022-10-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfapplication/pdfapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/pdfapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheethttp://hdl.handle.net/20.500.12105/18896reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 789055open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/188962026-06-12T12:43:37Z
dc.title.none.fl_str_mv The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
title The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
spellingShingle The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
Beucher, Anthony
Hepatocyte Nuclear Factor 1-alpha
Promoter Regions, Genetic
RNA, Long Noncoding
Animals
Humans
Mice
Mammals
Transcription, Genetic
title_short The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
title_full The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
title_fullStr The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
title_full_unstemmed The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
title_sort The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A.
dc.creator.none.fl_str_mv 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
author Beucher, Anthony
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv UK Research and Innovation
Wellcome Trust
Unión Europea. Comisión Europea. European Research Council (ERC)
Ministerio de Ciencia y Universidades (España)
NIHR - Imperial Biomedical Research Centre (Reino Unido)
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
Centres de Recerca de Catalunya (CERCA)
dc.subject.none.fl_str_mv Hepatocyte Nuclear Factor 1-alpha
Promoter Regions, Genetic
RNA, Long Noncoding
Animals
Humans
Mice
Mammals
Transcription, Genetic
topic Hepatocyte Nuclear Factor 1-alpha
Promoter Regions, Genetic
RNA, Long Noncoding
Animals
Humans
Mice
Mammals
Transcription, Genetic
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-10-01
2022
2022-10-01
2024
2024-03-07
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/18896
url http://hdl.handle.net/20.500.12105/18896
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 789055
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/vnd.openxmlformats-officedocument.spreadsheetml.sheet
application/vnd.openxmlformats-officedocument.spreadsheetml.sheet
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dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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