title: Acute TNF-induced repression of cell identity genes is mediated by NFκB-directed redistribution of cofactors from super-enhancers.
abstract: The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) is directly involved and required for the acute activation of the inflammatory gene program. Here, we show that the major transactivating subunit of NFκB, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high-occupancy sites within super-enhancers. Based on these data, we have developed models that, with high accuracy, predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super-enhancers in a highly cell-type-specific manner. Our results propose a novel paradigm for NFκB-mediated repression, whereby NFκB selectively redistributes cofactors from high-occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Søren Fisker
authors.initials: SF
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Bjørk Ditlev
authors.initials: BD
authors.lastname: Larsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Anne
authors.initials: A
authors.lastname: Loft
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Ronni
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Jesper Grud Skat
authors.initials: JG
authors.lastname: Madsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D065150:Cellular Reprogramming / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D056913:Mediator Complex Subunit 1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D056913:Mediator Complex Subunit 1; D016328:NF-kappa B; D009687:Nuclear Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins