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Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):854-869. doi: 10.1161/ATVBAHA.117.310388. Epub 2018 Feb 15.

Inhibition of Endothelial NOTCH1 Signaling Attenuates Inflammation by Reducing Cytokine-Mediated Histone Acetylation at Inflammatory Enhancers.

Author information

1
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.).
2
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.). gharalds@rr-research.no.

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

Comment in

PMID:
29449332
DOI:
10.1161/ATVBAHA.117.310388
[Indexed for MEDLINE]

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