Mutations on a conserved distal enhancer in the porcine C-reactive protein gene impair its expression in liver

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• dc.contributor.author Hernández Banqué, Carles
• dc.contributor.author Jové-Juncà, Teodor
• dc.contributor.author Crespo-Piazuelo, Daniel
• dc.contributor.author González-Rodríguez, Olga
• dc.contributor.author Ramayo-Caldas, Yuliaxis
• dc.contributor.author Esteve-Codina, Anna
• dc.contributor.author Mercat, Marie-José
• dc.contributor.author Bink, Marco C. A. M.
• dc.contributor.author Quintanilla, Raquel
• dc.contributor.author Ballester Devís, Maria
• dc.date.accessioned 2024-01-18T10:09:17Z
• dc.date.available 2024-01-18T10:09:17Z
• dc.date.issued 2023
• dc.description.abstract C-reactive protein (CRP) is an evolutionary highly conserved protein. Like humans, CRP acts as a major acute phase protein in pigs. While CRP regulatory mechanisms have been extensively studied in humans, little is known about the molecular mechanisms that control pig CRP gene expression. The main goal of the present work was to study the regulatory mechanisms and identify functional genetic variants regulating CRP gene expression and CRP blood levels in pigs. The characterization of the porcine CRP proximal promoter region revealed a high level of conservation with both cow and human promoters, sharing binding sites for transcription factors required for CRP expression. Through genome-wide association studies and fine mapping, the most associated variants with both mRNA and protein CRP levels were localized in a genomic region 39.3 kb upstream of CRP. Further study of the region revealed a highly conserved putative enhancer that contains binding sites for several transcriptional regulators such as STAT3, NF-kB or C/EBP-β. Luciferase reporter assays showed the necessity of this enhancer-promoter interaction for the acute phase induction of CRP expression in liver, where differences in the enhancer sequences significantly modified CRP activity. The associated polymorphisms disrupted the putative binding sites for HNF4α and FOXA2 transcription factors. The high correlation between HNF4α and CRP expression levels suggest the participation of HNF4α in the regulatory mechanism of porcine CRP expression through the modification of its binding site in liver. Our findings determine, for the first time, the relevance of a distal regulatory element essential for the acute phase induction of porcine CRP in liver and identify functional polymorphisms that can be included in pig breeding programs to improve immunocompetence.
• dc.description.sponsorship The authors declare financial support was received for the research, authorship, and/or publication of this article. The study was funded by grants AGL2016-75432-R and PID2020-112677RB-C21 awarded by MCIN/AEI/10.13039/501100011033 and GENE-SWitCH project (https://www.gene-switch.eu), which is funded by the European Union’s Horizon 2020 Research and Innovation Programme under the grant agreement n°817998. T. Jové-Juncà was funded with an IRTA fellowship (CPI1221) and C. Hernández-Banqué was supported by a FPI grant (PRE2021-097825) granted by the Spanish Ministry of Science and Innovation. YR-C was financially supported by a Ramon y Cajal contract (RYC2019-027244-I) from the Spanish Ministry of Science and Innovation. The authors are part to a Consolidated Research Group AGAUR, with the reference 2021-SGR-01552.
• dc.format.mimetype application/pdf
• dc.identifier.citation Hernández-Banqué C, Jové-Juncà T, Crespo-Piazuelo D, González-Rodríguez O, Ramayo-Caldas Y, Esteve-Codina A, Mercat MJ, Bink MCAM, Quintanilla R, Ballester M. Mutations on a conserved distal enhancer in the porcine C-reactive protein gene impair its expression in liver. Front Immunol. 2023 Sep 14;14:1250942. DOI: 10.3389/fimmu.2023.1250942
• dc.identifier.doi http://dx.doi.org/10.3389/fimmu.2023.1250942
• dc.identifier.issn 1664-3224
• dc.identifier.uri http://hdl.handle.net/10230/58751
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Front Immunol. 2023 Sep 14;14:1250942
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/817998
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/AGL2016-75432-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-112677RB-C21
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PRE2021-097825
• dc.rights © 2023 Hernández-Banqué, Jové-Juncà, Crespo-Piazuelo, González-Rodríguez, Ramayo-Caldas, Esteve-Codina, Mercat, Bink, Quintanilla and Ballester. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword C-reactive protein
• dc.subject.keyword RNA-seq
• dc.subject.keyword Enhancer
• dc.subject.keyword Fine-mapping
• dc.subject.keyword Luciferase assays
• dc.subject.keyword Pig
• dc.title Mutations on a conserved distal enhancer in the porcine C-reactive protein gene impair its expression in liver
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion