Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA231765 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1050720_1.fastq.gz | Fastqsanger.gz | |||
| SRR1050720_2.fastq.gz | Fastqsanger.gz | |||
| SRR1050721_1.fastq.gz | Fastqsanger.gz | |||
| SRR1050721_2.fastq.gz | Fastqsanger.gz | |||
| SRR1050722_1.fastq.gz | Fastqsanger.gz |
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Project description:Background The rearrangement of nucleosomes along the DNA fiber profoundly affects gene expression, but little is known about how signaling reshapes the chromatin landscape, in 3D space and over time, to allow the establishment of new transcriptional programs. Results Using micrococcal nuclease treatment and high-throughput sequencing, we map genome-wide changes in nucleosome positioning in primary human endothelial cells stimulated with tumour necrosis factor alpha (TNFalpha) - a proinflammatory cytokine that signals through nuclear factor kappaB (NF-kappaB). Within 10 minutes, nucleosomes reposition at regions both proximal and distal to NF-kappaB binding sites, before the transcription factor quantitatively binds thereon. Similarly, in long TNFalpha-responsive genes, repositioning precedes transcription by pioneering elongating polymerases and appears to nucleate from intragenic enhancer clusters resembling super-enhancers. By 30 minutes, widespread repositioning occurs throughout Mbp-long chromosomal segments, with consequential effects on 3D structure, detected using chromosome conformation capture. Conclusions Whilst nucleosome repositioning is viewed as a local phenomenon, our results point to effects occurring over multiple scales. Here, we present data in support of a TNFalpha-induced priming mechanism, mostly independent of NF-kappaB binding and/or elongating RNA polymerases, leading to a plastic network of interactions that affects DNA accessibility over large domains. MNase-Seq of HUVEC cells after stimulation with TNFα for 0, 10 or 30 min. Biological replicates for 0 and 30 min.
2014-11-05 | E-GEOD-53343 | biostudies-arrayexpress
Project description:Background The rearrangement of nucleosomes along the DNA fiber profoundly affects gene expression, but little is known about how signaling reshapes the chromatin landscape, in 3D space and over time, to allow the establishment of new transcriptional programs. Results Using micrococcal nuclease treatment and high-throughput sequencing, we map genome-wide changes in nucleosome positioning in primary human endothelial cells stimulated with tumour necrosis factor alpha (TNFalpha) - a proinflammatory cytokine that signals through nuclear factor kappaB (NF-kappaB). Within 10 minutes, nucleosomes reposition at regions both proximal and distal to NF-kappaB binding sites, before the transcription factor quantitatively binds thereon. Similarly, in long TNFalpha-responsive genes, repositioning precedes transcription by pioneering elongating polymerases and appears to nucleate from intragenic enhancer clusters resembling super-enhancers. By 30 minutes, widespread repositioning occurs throughout Mbp-long chromosomal segments, with consequential effects on 3D structure, detected using chromosome conformation capture. Conclusions Whilst nucleosome repositioning is viewed as a local phenomenon, our results point to effects occurring over multiple scales. Here, we present data in support of a TNFalpha-induced priming mechanism, mostly independent of NF-kappaB binding and/or elongating RNA polymerases, leading to a plastic network of interactions that affects DNA accessibility over large domains.
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Project description:Prostaglandin E2 (PGE2) is involved in several inflammatory conditions including periodontitis. The aim of this study was to investigate the global gene expression profile of tumor necrosis factor alpha (TNFalpha) stimulated human gingival fibroblasts, focusing on signal pathways related to PGE2 production and the new PGE2-synthesizing enzymes, prostaglandin E synthases (PGES). The expression of microsomal prostaglandin E synthase-1 (mPGES-1) as well as the upstream cyclooxygenase-2 (COX-2) was up-regulated by TNFalpha, accompanied by increased PGE2 production. In contrast, the expression of microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFalpha. Using microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, we identified differentially expressed genes in response to TNFalpha treatment. Enrichment analysis of microarray data identified two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappaB (NF-kappaB). We used specific inhibitors and phosphorylation analysis to confirm their role in PGE2 regulation. Both JNK and NF-kappaB inhibitors reduced the TNFalpha-stimulated up-regulation of mPGES-1 and COX-2 as well as subsequent PGE2 production. The novel finding that TNFalpha-stimulated mPGES-1 is regulated by JNK suggests this kinase as a potential future target for treatment strategies in inflammatory disorders, including periodontitis. Keywords: Time course, gene expression, factorial design.
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Project description:To test whether cholesterol overload in smooth muscle cells (SMCs) drives NF-kappaB signaling and to map target genes controlled by NF-kappaB signaling in SMCs, we cultured primary aortic SMCs from wildtype mice in the presence of cyclodextrin-complexed cholesterol or the prototypical NF-kappaB activator tumor necrosis factor (TNF) with or without blocking canonical NF-kappaB signaling by knockdown of inhibitor of kappaB kinase beta (Ikbkb).
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Project description:Tumor necrosis factor alpha (TNFalpha) plays an important role in immune regulation, inflammation, and autoimmunity. Chronic TNFalpha exposure has been shown to down-modulate T cell responses. In a mouse T cell hybridoma model, TNFalpha attenuated T cell receptor (TCR) signaling. We have confirmed that chronic TNFalpha and anti-TNFalpha exposure suppressed and increased T cell responses in BDC2.5 CD4+ T cells, respectively. The goal of this study is to analyze global transcriptional alterations resulting from TNFalpha treatment on TCR signaling pathways using cDNA microarrays. We found that genes involved in functional categories including T cell signaling, cell cycle, proliferation, ubiquitination, cytokine synthesis, calcium signaling, and apoptosis were modulated. Genes such as ubiquitin family genes, cytokine inducible SH2-containing genes, cyclin-dependent kinase inhibitors p21, p57, calmodulin family genes (calmodulin -V1, -V2, and ?V3) and calcium channel voltage- dependent, N type alpha1B subunit (CaV2.2) were induced by TNFalpha, while Vav2, Rho GTPase activating protein, calcium channel voltage dependent, L type alpha 1C subunit (CaV1.2), interleukin-1 (IL) receptor-associated kinase 1, and -V2 (IRAK-1and -2) and IL enhancer binding factor 3 were reduced by TNFalpha. Genes such as CaV1.2 and proliferating cell nuclear antigen, repressed by TNFalpha, were induced by anti-TNF treatment. Further, we showed that chronic TNFalpha exposure impaired NF-kappaB and AP-1 transactivation activity, leading to T cell unresponsiveness. Thus, our results present a detailed picture of transcriptional programs affected by chronic TNFalpha exposure, and provide candidate target genes, which may function to mediate TNFalpha induced T cell unresponsiveness. Set of arrays that are part of repeated experiments Keywords: Biological Replicate
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Project description:Signal transduction by the NF-kappaB pathway is a key regulator of a host of cellular responses to extracellular and intracellular messages. The NEMO adaptor protein lies at the top of this pathway and serves as a molecular conduit, connecting signals transmitted from upstream sensors to the downstream NF-kappaB transcription factor and subsequent gene activation. The position of NEMO within this pathway makes it an attractive target from which to search for new proteins that link NF-kappaB signaling to additional pathways and upstream effectors. In this work, we have used protein microarrays to identify novel NEMO interactors. A total of 112 protein interactors were identified, with the most statistically significant hit being the canonical NEMO interactor IKKbeta, with IKKalpha also being identified. Of the novel interactors, more than 30% were kinases, while at least 25% were involved in signal transduction. Binding of NEMO to several interactors, including CALB1, CDK2, SAG, SENP2 and SYT1, was confirmed using GST pulldown assays and coimmunoprecipitation, validating the initial screening approach. Overexpression of CALB1, CDK2 and SAG was found to stimulate transcriptional activation by NF-kappaB, while SYT1 overexpression repressed TNFalpha-dependent NF-kappaB transcriptional activation in human embryonic kidney cells. Corresponding with this finding, RNA silencing of CDK2, SAG and SENP2 reduced NF-kappaB transcriptional activation, supporting a positive role for these proteins in the NF-kappaB pathway. The identification of a host of new NEMO interactors opens up new research opportunities to improve understanding of this essential cell signaling pathway. For microarray screening, Invitrogen Protoarray v4.0 protein microarrays were used. Human NEMO expressed as a C-terminal GST fusion was purified from E. coli lysates and labelled with biotin. NEMO or biotinylated GST were applied to the microarrays and binding partners detected using streptavidin-Alexa Fluor 647. Significant interactors on both arrays were detected using Invitrogen Protoarray Prospector software and a Z-score cutoff of 3.0. Following subtraction of interactors present on the GST control array, a final set of significant NEMO interactors was derived. Full experimental details are supplied in Fenner, B. J., Scannell, M. & Prehn, J. H. M. (2010). Expanding the substantial interactome of NEMO using protein microarrays. PLoS ONE (in press).
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