Inhibition of Endothelial NOTCH1 Signaling Attenuates Inflammation by Reducing Cytokine-Mediated Histone Acetylation at Inflammatory Enhancers.
Arterioscler Thromb Vasc Biol, 2018/04;38(4):854-869.
Poulsen LC[1], Edelmann RJ[1], Krüger S[1], Diéguez-Hurtado R[1], Shah A[1], Stav-Noraas TE[1], Renzi A[1], Szymanska M[1], Wang J[1], Ehling M[1], Benedito R[1], Kasprzycka M[1], Bækkevold E[1], Sundnes O[1], Midwood KS[1], Scott H[1], Collas P[1], Siebel CW[1], Adams RH[1], Haraldsen G[2], Sundlisæter E[1], Hol J[1]
Affiliations
PMID: 29449332DOI: 10.1161/ATVBAHA.117.310388
Impact factor: 10.514
Abstract
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.
Keywords: animals; endothelial cells; inflammation; mice; mutation
MeSH terms
Acetylation; Animals; Appendicitis; Cells, Cultured; Dermatitis, Contact; Dipeptides; Disease Models, Animal; Endothelial Cells; Female; Gene Expression Regulation; Histones; Human Umbilical Vein Endothelial Cells; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Inflammation; Interleukin-1beta; Male; Mice, Inbred C57BL; Mice, Transgenic; Phenotype; Receptor, Notch1; Signal Transduction; Transcription Factor RelA
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