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The TNF receptor super family - NF-κB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues [RNA-seq]

ABSTRACT: After exiting the thymus, Foxp3+ regulatory T (Treg) cells undergo further differentiation in the periphery resulting in the generation of effector (e)Treg cells, a process dependent on TCR signaling and the transcription factor IRF4. Here we show tumor necrosis factor receptor super family (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA and induced expansion and survival of eTreg cells in lymphoid and non-lymphoid tissues, including RORγt+ resident Treg cells in the small intestine. RelA regulated basic cellular processes in Treg cells, including cell survival and proliferation in response to TNFRSF signaling, but was not required for IRF4 expression or DNA binding, indicating that both pathways operate independently. Importantly, a similar pathway appeared to be active in humans, as patients with a point mutation in NF-κB1, a binding partner of RelA, had severely compromised Treg cells. Therefore, although TCR signaling is essential for eTreg cell differentiation, the TNFRSF-NF-κB axis was additionally required in a non-redundant manner to maintain the pool of eTreg cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE98262 | GEO | 2017/08/28

SECONDARY ACCESSION(S): PRJNA384490

REPOSITORIES: GEO

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The TNF receptor super family - NF-κB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues [ChIP-seq]

Project description:After exiting the thymus, Foxp3+ regulatory T (Treg) cells undergo further differentiation in the periphery resulting in the generation of effector (e)Treg cells, a process dependent on TCR signaling and the transcription factor IRF4. Here we show tumor necrosis factor receptor super family (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA and induced expansion and survival of eTreg cells in lymphoid and non-lymphoid tissues, including RORγt+ resident Treg cells in the small intestine. RelA regulated basic cellular processes in Treg cells, including cell survival and proliferation in response to TNFRSF signaling, but was not required for IRF4 expression or DNA binding, indicating that both pathways operate independently. Importantly, a similar pathway appeared to be active in humans, as patients with a point mutation in NF-κB1, a binding partner of RelA, had severely compromised Treg cells. Therefore, although TCR signaling is essential for eTreg cell differentiation, the TNFRSF-NF-κB axis was additionally required in a non-redundant manner to maintain the pool of eTreg cells.

2017-08-28 | GSE98263 | GEO

RelA and RelB-dependent transcriptome analysis in lymphotoxin-ß receptor stimulated mouse embryonic fibroblasts

Project description:Background: Lymphotoxin signaling via the lymphotoxin-β receptor (LTβR) has been implicated in several biological processes, ranging from development of secondary lymphoid organs, maintenance of splenic tissue, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTβR crosslinking is NF-κB. Two signaling pathways have been described that result in the activation of classical p50-RelA and alternative p52-RelB NF-κB heterodimers. Results: Using microarray analysis, we investigated the transcriptional response downstream of the LTβR in mouse embryoni fibroblasts (MEF) and its regulation by the RelA and RelB subunits of NF-κB. We describe novel LTβR-responsive genes that are regulated by RelA and/or RelB. Interestingly, we found that the majority of LTβR-regulated genes require the presence of both RelA and RelB, suggesting significant crosstalk between the two NF-κB activation pathways. Gene Ontology (GO) analysis confirmed that LTβR-NF-κB target genes are predominantly involved in the regulation of immune responses. However, other biological processes, such as apoptosis/cell death, cell cycle, angiogenesis, and taxis were also regulated by LTβR signaling. Moreover, we show that activation of the LTβR inhibits the expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-γ (pparg), suggesting that LTβR signaling may interfere with adipogenic differentiation. Conclusions: Thus, microarray analysis of LTβR-stimulated fibroblasts revealed further insight into the transcriptional response of LTβR signaling and its regulation by the NF-κB family members RelA and RelB. Keywords: cell type comparison (wt vs relA-/- vs relB-/-) after genetic modification using a time course for each cell type (wt, relA-/-, relB-/-) two time points were analysed (0h as control and 10h) using 3 technical replicates resulting in 18 samples in total

2008-12-17 | E-GEOD-11963 | biostudies-arrayexpress

A pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics

Project description:Pseudogenes are thought to be inactive gene sequences, but recent evidence of extensive pseudogene transcription raised the question of potential function. Here we discover and characterize the sets of lncRNAs induced by inflammatory signaling via TNFα. TNFα regulates hundreds of lncRNAs, including 54 pseudogene lncRNAs, several of which show exquisitely selective expression in response to specific cytokines and microbial components in a NF-κB-dependent manner. Lethe, a pseudogene lncRNA, is selectively induced by proinflammatory cytokines via NF-κB or glucocorticoid receptor agonist, and functions in negative feedback signaling to NF-κB. Lethe interacts with NF-κB subunit RelA to inhibit RelA DNA binding and target gene activation. Lethe level decreases with organismal age, a physiological state associated with increased NF-κB activity. These findings suggest that expression of pseudogenes lncRNAs are actively regulated and constitute functional regulators of inflammatory signaling. RNA profiles of wild type (WT) MEFs treated with TNF-alpha were generated by deep sequencing using Illumina GAIIx. Examination of H3K4me3 histome modification in MEF.

2013-08-05 | E-GEOD-47494 | biostudies-arrayexpress

Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizers upon combined TNFR1/LTBR NF-kB signaling

Project description:Mouse aorta smooth muscle cells (SMCs) express TNF receptor superfamily member 1A (TNFR1) and lymphotoxin ß receptor (LTßR). Circumstantial evidence has linked the SMC LTßR to tertiary lymphoid organogenesis in diseased aortae of hyperlipidemic mice. Here, we explored potential roles of TNFR1 and LTßR activation in cultured SMCs. TNFR1 signaling by TNF activated the classical RelA NF-κB pathway, whereas LTßR signaling by agonistic anti LTßR antibody activated both the classical RelA and alternative RelB NF-κB pathways. Addition of both agonists synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB and promoted its nuclear translocation suggesting RelA-RelB cross-talk in transcription regulation. Correspondingly, microarrays showed that simultaneous TNFR1 and LTßR activation when compared to activation of single receptors was followed by markedly elevated levels of mRNAs encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Furthermore, SMCs acquired prototypical features of mesenchymal cells known as lymphoid tissue organizers (LTOs), which control tertiary lymphoid organogenesis in autoimmune diseases, through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, VCAM-1, and ICAM-1. Experiments with ltbr-/- SMCs suggested that the LTßR-RelB activation component of NF-κB signaling was obligatory to generate the LTO phenotype. TNFR1-LTßR crosstalk also resulted in augmented synthesis and prolonged secretion of lymphorganogenic chemokine proteins into the culture medium. Thus, combined TNFR1-LTßR signaling triggers SMC transdifferentiation into a phenotype that strikingly resembles LTOs. LTO-like SMCs may adopt a thus far unrecognized role in diseased arteries, i.e. to coordinate tertiary lymphoid organogenesis in atherosclerosis, aortic aneurysm, and transplant vasculopathy.

2009-11-23 | GSE15062 | GEO

Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation [RNA-seq]

Project description:Transcription factor NF-κB regulates cellular responses to environmental cues. For many stimuli NF-κB resides only transiently in the nucleus. Consequently, time-dependent transcriptional outputs are a fundamental feature of NF-κB activation. Here we identify mechanisms that direct kinetic patterns of NF-κB-dependent gene expression and transcriptional outcomes in response to a transient NF-κB-inducing stimulus in B cells. By combining RELA binding, RNA polymerase II (Pol II) recruitment, and perturbation of NF-κB activation, we demonstrate that kinetic differences amongst early- and late-activated RELA target genes can be understood based on chromatin configuration prior to cell activation and RELA-dependent priming, respectively. Additionally, we identified genes that were repressed by RELA activation and others that responded to RELA-activated transcription factors. Cumulatively, our studies define an NF-κB-responsive inducible gene cascade in activated B cells.

2018-09-17 | GSE117254 | GEO

Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation [ChIP-seq]

2018-09-17 | GSE117250 | GEO

Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation [ChIA-PET]

2018-09-17 | GSE117241 | GEO

A single Thr505 phospho-site mutation reveals an important role for the RelA NF-κB subunit in liver regeneration and cancer

Project description:Post-translational modification of NF-κB subunits provides a mechanism to differentially regulate their activity in response to the many stimuli that can induce this pathway. However, the physiological significance of these modifications is largely unknown and it remains unclear if these have a critical role in the normal and pathological functions of NF-κB in vivo. Among these, phosphorylation of the RelA(p65) Thr505 residue has been described as an important regulator of NF-κB activity in cell lines but its physiological significance was not known. Therefore, to learn more about the role of this pathway in vivo, we generated a knockin mouse with a RelA T505A mutation. Unlike RelA knockout mice, the RelA T505A mice develop normally but exhibit aberrant hepatocyte proliferation following liver partial hepatectomy or damage resulting from carbon tetrachloride treatment. Consistent with these effects, RelA T505A mice exhibit earlier onset of cancer in the N-nitrosodiethylamine (DEN) model of hepatocellular carcinoma. This data reveals a critical pathway controlling NF-κB function in the liver that acts to suppress tumour-promoting activities of RelA.

2015-11-30 | E-MTAB-3596 | biostudies-arrayexpress

Multi-species RELA ChIP-seq of mammalian aortic endothelial cells before and after TNFα stimulation

Project description:TNFα has an evolutionary conserved role in mediating inflammation via activation of the transcription factor NF-κB. The functions of individual NF-κB binding sites are not well understood. To identify conserved and functionally important NF-κB binding sites in mammals, we performed ChIP-seq to map the genome-wide binding of RELA and select histone modifications in primary vascular endothelial cells (ECs) isolated from the aortas of human (HAEC), mouse (MAEC) and cow (BAEC), before and after TNFα. The conserved RELA binding sites show strong epigenetic changes in response to TNFα and enrich near genes controlling vascular development and pro-inflammatory responses. Our method identifies novel modes of RELA-chromatin interactions that are conserved in mammals and shared between multiple cell-types. Particularly, genomic regions bound by RELA prior to stimulation are important responders during TNFα stimulation. We use CRISPR/Cas9 genome editing to validate the roles of the conserved RELA pre-bound sites near pro-inflammatory genes such as CCL2 and PLK2. Our evolutionary approach describes new aspects of mammalian NF-κB biology including its role within super-enhancers and relevance in inflammatory disorders.

2020-10-03 | E-MTAB-7889 | biostudies-arrayexpress

RelA and RelB-dependent transcriptome analysis in lymphotoxin-ß receptor stimulated mouse embryonic fibroblasts

2008-12-18 | GSE11963 | GEO

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