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Type I IFNs and TNF Cooperatively Reprogram Epigenomic Landscape of Human Macrophages to Promote Inflammatory Activation [RNA-seq]

ABSTRACT: Crossregulation of TLR responses by cytokines is essential for effective host defense, avoidance of toxicity, and homeostasis, but underlying mechanisms are not well understood. A comprehensive approach integrating RNA-seq, ChIP-seq and ATAC-seq digital footprinting showed that TNF and type I IFNs extensively remodel chromatin states in human macrophages to differentially regulate transcriptional induction of NF-κB, STAT, antiviral, and metabolic genes by LPS. IFN-α potentiated TNF inflammatory function by abrogating feedback silencing of inflammatory genes via priming of chromatin to enable robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings provide insights into epigenomic mechanisms by which cytokines reprogram inflammatory responses, and identify new functions and mechanisms of action of TNF and IFNs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100382 | GEO | 2017/06/23

SECONDARY ACCESSION(S): PRJNA391490

REPOSITORIES: GEO

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Type I IFNs and TNF Cooperatively Reprogram Epigenomic Landscape of Human Macrophages to Promote Inflammatory Activation [ATAC-seq]

Project description:Crossregulation of TLR responses by cytokines is essential for effective host defense, avoidance of toxicity, and homeostasis, but underlying mechanisms are not well understood. A comprehensive approach integrating RNA-seq, ChIP-seq and ATAC-seq digital footprinting showed that TNF and type I IFNs extensively remodel chromatin states in human macrophages to differentially regulate transcriptional induction of NF-κB, STAT, antiviral, and metabolic genes by LPS. IFN-α potentiated TNF inflammatory function by abrogating feedback silencing of inflammatory genes via priming of chromatin to enable robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings provide insights into epigenomic mechanisms by which cytokines reprogram inflammatory responses, and identify new functions and mechanisms of action of TNF and IFNs.

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Type I IFNs and TNF Cooperatively Reprogram Epigenomic Landscape of Human Macrophages to Promote Inflammatory Activation

Project description:Type I IFNs and TNF Cooperatively Reprogram Epigenomic Landscape of Human Macrophages to Promote Inflammatory Activation

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Type I IFNs facilitate innate immune control of opportunistic bacteria in the macrophage cytosol

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Project description:Proinflammatory stimuli rapidly and globally remodel chromatin landscape, thereby enabling transcriptional responses. Yet, the mechanisms coupling chromatin regulators to the master regulatory inflammatory transcription factor NF-kB remain poorly understood. We report in human endothelial cells (ECs) that activated NF-kB binds to enhancers, provoking a rapid, global redistribution of BRD4 preferentially at super-enhancers, large enhancer domains highly bound by chromatin regulators. Newly established NF-kB super-enhancers drive nearby canonical inflammatory response genes. In both ECs and macrophages BET bromodomain inhibition prevents super-enhancer formation downstream of NF-kB activation, abrogating proinflammatory transcription. In TNFa-activated endothelium this culminates in functional suppression of leukocyte rolling, adhesion and transmigration. Sustained BET bromodomain inhibitor treatment of LDLr -/- animals suppresses atherogenesis, a disease process rooted in pathological vascular inflammation involving endothelium and macrophages. These data establish BET-bromodomains as key effectors of inflammatory response through their role in the dynamic, global reorganization of super-enhancers during NF-kB activation. Gene expression analysis of human endothelial cells in resting state, treatment with TNFalpha or TNFalpha with the BET bromodomain inhibitor JQ1

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NF-kB coordinates rapid, BRD4-dependent remodeling of proinflammatory super-enhancers [ChIP-Seq]

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