title: Epigenetic Regulation of Early- and Late-Response Genes in Acute Pancreatitis.
abstract: Chromatin remodeling seems to regulate the patterns of proinflammatory genes. Our aim was to provide new insights into the epigenetic mechanisms that control transcriptional activation of early- and late-response genes in initiation and development of severe acute pancreatitis as a model of acute inflammation. Chromatin changes were studied by chromatin immunoprecipitation analysis, nucleosome positioning, and determination of histone modifications in promoters of proinflammatory genes in vivo in the course of taurocholate-induced necrotizing pancreatitis in rats and in vitro in rat pancreatic AR42J acinar cells stimulated with taurocholate or TNF-α. Here we show that the upregulation of early and late inflammatory genes rely on histone acetylation associated with recruitment of histone acetyltransferase CBP. Chromatin remodeling of early genes during the inflammatory response in vivo is characterized by a rapid and transient increase in H3K14ac, H3K27ac, and H4K5ac as well as by recruitment of chromatin-remodeling complex containing BRG-1. Chromatin remodeling in late genes is characterized by a late and marked increase in histone methylation, particularly in H3K4. JNK and p38 MAPK drive the recruitment of transcription factors and the subsequent upregulation of early and late inflammatory genes, which is associated with nuclear translocation of the early gene Egr-1 In conclusion, specific and strictly ordered epigenetic markers such as histone acetylation and methylation, as well as recruitment of BRG-1-containing remodeling complex are associated with the upregulation of both early and late proinflammatory genes in acute pancreatitis. Our findings highlight the importance of epigenetic regulatory mechanisms in the control of the inflammatory cascade.
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Valencia, 46100 Valencia, Spain.
authors: Juan
authors: 0000-0002-2041-4038
authors: J
authors: Sandoval
authors: Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Valencia, Spain; and.
authors: Javier
authors: J
authors: Pereda
authors: Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Valencia, Spain; and.
authors: Salvador
authors: S
authors: Pérez
authors: Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Valencia, Spain; and.
authors: Isabela
authors: I
authors: Finamor
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Valencia, 46100 Valencia, Spain.|Institute of Health Research INCLIVA (Foundation for Research of the Clinic Hospital of the "Comunidad Valenciana"), 46010 Valencia, Spain.
authors: Azahara
authors: A
authors: Vallet-Sánchez
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Valencia, 46100 Valencia, Spain.
authors: José Luis
authors: JL
authors: Rodríguez
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Valencia, 46100 Valencia, Spain.|Institute of Health Research INCLIVA (Foundation for Research of the Clinic Hospital of the "Comunidad Valenciana"), 46010 Valencia, Spain.
authors: Luis
authors: 0000-0001-9610-6448
authors: L
authors: Franco
authors: Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Valencia, Spain; and Juan.Sastre@uv.es.
authors: Juan
authors: J
authors: Sastre
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Valencia, 46100 Valencia, Spain.|Institute of Health Research INCLIVA (Foundation for Research of the Clinic Hospital of the "Comunidad Valenciana"), 46010 Valencia, Spain.
authors: Gerardo
authors: 0000-0001-8367-653X
authors: G
authors: López-Rodas
mesh_terms: D000107:Acetylation; D061354:Acinar Cells / Q000187:drug effects; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007249:Inflammation / Q000235:genetics; D008745:Methylation; D009687:Nuclear Proteins / Q000235:genetics; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D051381:Rats; D013656:Taurocholic Acid / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D006657:Histones; D009687:Nuclear Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D013656:Taurocholic Acid; D051548:Histone Acetyltransferases; C084108:SMARCA4 protein, human; D004265:DNA Helicases