Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster

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• dc.contributor.author Miguel Escalada, Irene
• dc.contributor.author Maestro, Miguel Ángel
• dc.contributor.author Balboa, Diego
• dc.contributor.author Elek, Anamaria
• dc.contributor.author Bernal, Aina
• dc.contributor.author Bernardo, Edgar
• dc.contributor.author Grau, Vanessa
• dc.contributor.author García-Hurtado, Javier
• dc.contributor.author Sebé-Pedrós, Arnau
• dc.contributor.author Ferrer, Jorge
• dc.date.accessioned 2022-10-26T06:25:41Z
• dc.date.available 2022-10-26T06:25:41Z
• dc.date.issued 2022
• dc.description.abstract Sequence variants in cis-acting enhancers are important for polygenic disease, but their role in Mendelian disease is poorly understood. Redundancy between enhancers that regulate the same gene is thought to mitigate the pathogenic impact of enhancer mutations. Recent findings, however, have shown that loss-of-function mutations in a single enhancer near PTF1A cause pancreas agenesis and neonatal diabetes. Using mouse and human genetic models, we show that this enhancer activates an entire PTF1A enhancer cluster in early pancreatic multipotent progenitors. This leading role, therefore, precludes functional redundancy. We further demonstrate that transient expression of PTF1A in multipotent progenitors sets in motion an epigenetic cascade that is required for duct and endocrine differentiation. These findings shed insights into the genome regulatory mechanisms that drive pancreas differentiation. Furthermore, they reveal an enhancer that acts as a regulatory master key and is thus vulnerable to pathogenic loss-of-function mutations.
• dc.description.sponsorship This research was supported by Ministerio de Ciencia e Innovación (BFU2014-54284-R, RTI2018-095666-B-I00), Medical Research Council (MR/L02036X/1), a Wellcome Trust Senior Investigator Award (WT101033), European Research Council Advanced Grant (789055), and CIBERDEM-Instituto de Salud Carlos III. Research in A.S.-P. group was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme Grant Agreement (851647).
• dc.format.mimetype application/pdf
• dc.identifier.citation Miguel-Escalada I, Maestro MÁ, Balboa D, Elek A, Bernal A, Bernardo E, Grau V, García-Hurtado J, Sebé-Pedrós A, Ferrer J. Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster. Dev Cell. 2022 Aug 22;57(16):1922-36.e9. DOI: 10.1016/j.devcel.2022.07.014
• dc.identifier.doi http://dx.doi.org/10.1016/j.devcel.2022.07.014
• dc.identifier.issn 1534-5807
• dc.identifier.uri http://hdl.handle.net/10230/54592
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Dev Cell. 2022 Aug 22;57(16):1922-36.e9
• 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.relation.projectID info:eu-repo/grantAgreement/EC/H2020/851647
• dc.rights © 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (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 Mendelian disease
• dc.subject.keyword NEUROG3
• dc.subject.keyword PTF1A
• dc.subject.keyword Diabetes mellitus
• dc.subject.keyword Endocrine differentiation
• dc.subject.keyword Enhancers
• dc.subject.keyword Non-coding mutations
• dc.subject.keyword Pancreas development
• dc.subject.keyword Stem cell differentiation
• dc.title Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion