Inhibition of Endothelial NOTCH1 Signaling Attenuates Inflammation by Reducing Cytokine-Mediated Histone Acetylation at Inflammatory Enhancers
| Autor: | Rui Benedito, Kim S. Midwood, Monika Szymanska, Ralf H. Adams, Tor Espen Stav-Noraas, Christian W. Siebel, Eirik Sundlisæter, Anastasia Renzi, Helge Scott, Monika Kasprzycka, Manuel Ehling, Johanna Hol, Lars La Cour Poulsen, Espen S. Baekkevold, Olav Sundnes, Reidunn J Edelmann, Rodrigo Diéguez-Hurtado, Philippe Collas, Akshay Shah, Guttorm Haraldsen, Stig Krüger, Junbai Wang |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment Interleukin-1beta Mice Transgenic Inflammation Dermatitis Contact Histones 03 medical and health sciences Human Umbilical Vein Endothelial Cells medicine Animals Humans Receptor Notch1 Enhancer Cells Cultured biology Chemistry Transcription Factor RelA Endothelial Cells Interleukin Acetylation Dipeptides Appendicitis Chromatin Cell biology Mice Inbred C57BL Endothelial stem cell Disease Models Animal Phenotype 030104 developmental biology Histone Cytokine Gene Expression Regulation Immunoglobulin J Recombination Signal Sequence-Binding Protein embryonic structures cardiovascular system biology.protein Female biological phenomena cell phenomena and immunity Signal transduction medicine.symptom Cardiology and Cardiovascular Medicine Signal Transduction |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 38:854-869 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.117.310388 |
| Popis: | Objective— Endothelial upregulation of adhesion molecules serves to recruit leukocytes to inflammatory sites and appears to be promoted by NOTCH1; however, current models based on interactions between active NOTCH1 and NF-κB components cannot explain the transcriptional selectivity exerted by NOTCH1 in this context. Approach and Results— Observing that Cre/Lox-induced conditional mutations of endothelial Notch modulated inflammation in murine contact hypersensitivity, we found that IL (interleukin)-1β stimulation induced rapid recruitment of RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A) to genomic sites occupied by NOTCH1-RBPJ (recombination signal-binding protein for immunoglobulin kappa J region) and that NOTCH1 knockdown reduced histone H3K27 acetylation at a subset of NF-κB–directed inflammatory enhancers. Conclusions— Our findings reveal that NOTCH1 signaling supports the expression of a subset of inflammatory genes at the enhancer level and demonstrate how key signaling pathways converge on chromatin to coordinate the transition to an infla mmatory endothelial phenotype. |
| Databáze: | OpenAIRE |
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