Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics

Abstract Retinoic acid (RA) is a key signal for the specification of the pancreas. Still, the gene regulatory cascade triggered by RA in the endoderm remains poorly characterized. In this study, we investigated this regulatory network in zebrafish by combining RNA-seq, RAR ChIP-seq and ATAC-seq assa...

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Autores principales:	Ana R. López-Pérez, Piotr J. Balwierz, Boris Lenhard, Ferenc Muller, Fiona C. Wardle, Isabelle Manfroid, Marianne L. Voz, Bernard Peers
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/850bfa32b31943dd9ae0d3bdc4010ac4
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spelling	oai:doaj.org-article:850bfa32b31943dd9ae0d3bdc4010ac42021-11-28T12:16:48ZIdentification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics10.1038/s41598-021-02039-y2045-2322https://doaj.org/article/850bfa32b31943dd9ae0d3bdc4010ac42021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02039-yhttps://doaj.org/toc/2045-2322Abstract Retinoic acid (RA) is a key signal for the specification of the pancreas. Still, the gene regulatory cascade triggered by RA in the endoderm remains poorly characterized. In this study, we investigated this regulatory network in zebrafish by combining RNA-seq, RAR ChIP-seq and ATAC-seq assays. By analysing the effect of RA and of the RA receptor (RAR) inverse-agonist BMS493 on the transcriptome and on the chromatin accessibility of endodermal cells, we identified a large set of genes and regulatory regions regulated by RA signalling. RAR ChIP-seq further defined the direct RAR target genes in zebrafish, including hox genes as well as several pancreatic regulators like mnx1, insm1b, hnf1ba and gata6. Comparison of zebrafish and murine RAR ChIP-seq data highlighted the conserved direct target genes and revealed that some RAR sites are under strong evolutionary constraints. Among them, a novel highly conserved RAR-induced enhancer was identified downstream of the HoxB locus and driving expression in the nervous system and in the gut in a RA-dependent manner. Finally, ATAC-seq data unveiled the role of the RAR-direct targets Hnf1ba and Gata6 in opening chromatin at many regulatory loci upon RA treatment.Ana R. López-PérezPiotr J. BalwierzBoris LenhardFerenc MullerFiona C. WardleIsabelle ManfroidMarianne L. VozBernard PeersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ana R. López-Pérez Piotr J. Balwierz Boris Lenhard Ferenc Muller Fiona C. Wardle Isabelle Manfroid Marianne L. Voz Bernard Peers Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics
description	Abstract Retinoic acid (RA) is a key signal for the specification of the pancreas. Still, the gene regulatory cascade triggered by RA in the endoderm remains poorly characterized. In this study, we investigated this regulatory network in zebrafish by combining RNA-seq, RAR ChIP-seq and ATAC-seq assays. By analysing the effect of RA and of the RA receptor (RAR) inverse-agonist BMS493 on the transcriptome and on the chromatin accessibility of endodermal cells, we identified a large set of genes and regulatory regions regulated by RA signalling. RAR ChIP-seq further defined the direct RAR target genes in zebrafish, including hox genes as well as several pancreatic regulators like mnx1, insm1b, hnf1ba and gata6. Comparison of zebrafish and murine RAR ChIP-seq data highlighted the conserved direct target genes and revealed that some RAR sites are under strong evolutionary constraints. Among them, a novel highly conserved RAR-induced enhancer was identified downstream of the HoxB locus and driving expression in the nervous system and in the gut in a RA-dependent manner. Finally, ATAC-seq data unveiled the role of the RAR-direct targets Hnf1ba and Gata6 in opening chromatin at many regulatory loci upon RA treatment.
format	article
author	Ana R. López-Pérez Piotr J. Balwierz Boris Lenhard Ferenc Muller Fiona C. Wardle Isabelle Manfroid Marianne L. Voz Bernard Peers
author_facet	Ana R. López-Pérez Piotr J. Balwierz Boris Lenhard Ferenc Muller Fiona C. Wardle Isabelle Manfroid Marianne L. Voz Bernard Peers
author_sort	Ana R. López-Pérez
title	Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics
title_short	Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics
title_full	Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics
title_fullStr	Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics
title_full_unstemmed	Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics
title_sort	identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/850bfa32b31943dd9ae0d3bdc4010ac4
work_keys_str_mv	AT anarlopezperez identificationofdownstreameffectorsofretinoicacidspecifyingthezebrafishpancreasbyintegrativegenomics AT piotrjbalwierz identificationofdownstreameffectorsofretinoicacidspecifyingthezebrafishpancreasbyintegrativegenomics AT borislenhard identificationofdownstreameffectorsofretinoicacidspecifyingthezebrafishpancreasbyintegrativegenomics AT ferencmuller identificationofdownstreameffectorsofretinoicacidspecifyingthezebrafishpancreasbyintegrativegenomics AT fionacwardle identificationofdownstreameffectorsofretinoicacidspecifyingthezebrafishpancreasbyintegrativegenomics AT isabellemanfroid identificationofdownstreameffectorsofretinoicacidspecifyingthezebrafishpancreasbyintegrativegenomics AT mariannelvoz identificationofdownstreameffectorsofretinoicacidspecifyingthezebrafishpancreasbyintegrativegenomics AT bernardpeers identificationofdownstreameffectorsofretinoicacidspecifyingthezebrafishpancreasbyintegrativegenomics
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Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics

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