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Characterization of changes in enhancer activity and transcription factor binding following pro-inflammatory cytokine treatments in primary mouse hepatocytes

ABSTRACT: The cytokines interleukin 1β and 6 (IL-1β, IL-6) mediate the systemic acute and chronic inflammatory response. In liver, they both regulate the secretion of acute-phase proteins which curb infection and tissue damage. Using RNA-seq, we show that these cytokines regulate gene transcription in a multifaceted manner to modulate gene expression, leading both to synergistic and antagonistic expression patterns. By mapping changes in enhancer landscape and transcription factor occupancy following cytokine treatment, we show that synergistic gene expression was achieved by cooperation between cytokine-induced transcription factors on the chromatin template. At a subset of enhancers proximal to synergistically-induced acute-phase genes, IL-1β led to enhancer priming and an increase in STAT3 binding. These effects were mediated by NF-κB and were enhancer-specific rather that influencing the entirety of STAT3 binding. Our findings reveal that STAT3-NF-κB crosstalk at the chromatin template plays a major role in transcriptional regulation during inflammation

ORGANISM(S): Mus musculus

PROVIDER: GSE96767 | GEO | 2017/10/10

SECONDARY ACCESSION(S): PRJNA379600

REPOSITORIES: GEO

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Project description:Colitis is the common pathological lesion of inflammatory bowel diseases, the major chronic inflammatory diseases of intestinal tracts in humans. In this study, we investigated the therapeutic effects of ginger extract and its component zingerone in mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Mice were administered with TNBS and/or various amounts of ginger and zingerone by an intrarectal route. The severity of colitis was evaluated by colonic weight/length ratio, macroscopic lesion, and histological examination. The mechanisms of ginger and zingerone were further elucidated by DNA microarray, ex vivo imaging, and immunohistochemical staining. Our data showed that treatment with ginger extract and zingerone ameliorated TNBS-induced colonic inflammation and injury in a dose-dependent manner. Pathway analysis of ginger- and zingerone-regulated gene expression profiles showed that ginger and zingerone significantly regulated cytokine-related pathways. Network analysis showed that nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) were key molecules involved in the expression of ginger- and zingerone-affected genes. Ex vivo imaging and immunohistochemical staining further verified that ginger and zingerone suppressed TNBS-induced NF-κB activation and decreased the NF-κB and IL-1β protein levels in the colon. In conclusion, our data showed that ginger improved the TNBS-induced colitis in mice via modulation of NF-κB activity and IL-1β signaling pathway. Moreover, zingerone might be the active component of ginger responsible for the amelioration of colitis induced by TNBS. A total of 24 mice was randomly divided into four groups of six mice: mock, mice were given with 0.1 ml of 50% ethanol; TNBS, mice were given with 250 mg/kg TNBS in 0.1 ml of 50% ethanol; TNBS/ginger, mice were administered with mixtures containing 250 mg/kg TNBS and various amounts of ginger extract in 0.1 ml of 50% ethanol; TNBS/zingerone, mice were given with mixtures containing 250 mg/kg TNBS and various amounts of zingerone in 0.1 ml of 50% ethanol. Mice were sacrificed seven days later for histochemical staining, RNA extraction, and ex vivo imaging.

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Characterization of changes in enhancer activity and transcription factor binding following pro-inflammatory cytokine treatments in primary mouse hepatocytes

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