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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.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.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.

Original publication

DOI

10.1161/atvbaha.117.310388

Type

Journal article

Journal

Arteriosclerosis, thrombosis, and vascular biology

Publication Date

04/2018

Volume

38

Pages

854 - 869

Addresses

From the Department of Pathology, Oslo University Hospital Rikshospitalet (L.l.C.P., R.J.E., S.K., T.E.S.-N., A.R., M.S., J.W., M.K., E.B., O.S., H.S., G.H., E.S., J.H.), Department of Pathology, Institute for Clinical Medical Sciences (H.S., G.H.) and Department of Molecular Medicine, Institute for Basal Medical Sciences (A.S., P.C.), University of Oslo, Norway; Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, University of Münster, Germany (R.D.-H., M.E., R.B., R.H.A.); Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, United Kingdom (K.S.M.); and Department of Discovery Oncology, Genentech, Inc, South San Francisco, CA (C.W.S.).