Mutations on a conserved distal enhancer in the porcine C-reactive protein gene impair its expression in liver
Author
Hernández-Banqué, Carles
Jové-Juncà, Teodor
González-Rodríguez, Olga
Esteve-Codina, Anna
Mercat, Marie-José
Bink, Marco C. A. M.
Publication date
2023-09-14ISSN
1664-3224
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.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
575 - General genetics. General cytogenetics
Pages
11
Publisher
Frontiers Media
Is part of
Frontiers in Immunology
Citation
Hernández-Banqué, Carles, Teodor Jové-Juncà, Daniel Crespo-Piazuelo, Olga González‐Rodríguez, Yuliaxis Ramayo-Caldas, Anna Esteve‐Codina, Marie J. Mercat, Marco C.A.M. Bink, Raquel Quintanilla, and María Ballester. 2023. “Mutations on a Conserved Distal Enhancer in the Porcine C-Reactive Protein Gene Impair Its Expression in Liver.” Frontiers in Immunology 14 (September). https://doi.org/10.3389/fimmu.2023.1250942.
Grant agreement number
MINECO/Programa Estatal de I+D+I orientada a los retos de la sociedad/AGL2016-75432-R/ES/DETERMINACION GENETICA DE LA CAPACIDAD INMUNOLOGICA EN PORCINO: IDENTIFICACION DE VARIANTES GENETICAS FUNCIONALES PARA LA IMPLEMENTACION DE SELECCION GENOMICA/
MICINN/Programa Estatal de generación del conocimiento y fortalecimiento científico y tecnológico del sistema I+D+I y Programa Estatal de I+D+I orientada a los retos de la sociedad/PID2020-112677RB-C21/ES/FISIOLOGIA MOLECULAR DEL INMUNOMETABOLISMO EN PORCINO: BASES PARA LA SELECCION DE POBLACIONES MAS ROBUSTAS/
EC/H2020/817998/EU/The regulatory GENomE of SWine and CHicken: functional annotation during development/GENE-SWitCH
MICIU/Programa Estatal de promoción del talento y su empleabilidad en I+D+I/RYC2019-027244-I/ES/Metagenomics and integrative biology tools to improve sustainable livestock systems/
Program
Genètica i Millora Animal
This item appears in the following Collection(s)
- ARTICLES CIENTÍFICS [2555]
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