Variation of genome-wide NF-kappa B RELA binding sites in response to different microbial stimuli
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ABSTRACT:
PROVIDER: PRJNA356686 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below.
2018-01-30 | GSE91020 | GEO
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
Project description:Type 1 diabetes mellitus results from an autoimmune destruction of pancreatic beta-cells. Based on findings suggesting NF-kappa B plays a role in beta cell apoptosis, we blocked NF-kappa B activation in cytokine-exposed FACS sorted beta cells by a recombinant adenovirus (AdI kappa B((SA)2)) containing an inhibitor of NF kappa B alpha (I kappa Bac) super-repressor (S32A/S36A). The expression profile was then analyzed with the Affymetrix RG U34a microarray.
2006-06-16 | E-CBIL-9 | biostudies-arrayexpress
Project description:Using a mouse model with hepatocyte-specific deletion of transcription factor NF-κB RelA (p65), our group has previously revealed the important role of RelA in inducing the acute phase response, maintaining host defense, and preventing liver injury during sepsis. To goal of this study was determine the influence of RelA on hepatic gene changes that provide liver protection during infection. Mice were generated with functional deletion of NF-kappaB RelA (p56) in hepatocytes using a Cre-LoxP system. Mutant mice expressed Cre-recombinase under the transcriptional control of an albumin promotor and homozygous floxed RelA alleles. Wild type control mice lack the Cre-recombinase. Microarray analysis was performed on liver RNA collected from both genotypes of mice in the absence and presence of pneumococcal bacteremia.
2019-06-07 | GSE126642 | GEO
Project description:NFKB is a family of transcription factors (TF), which are master regulators of the innate immune system. It is activated downstream of pathogen recognition receptors after ligand binding and regulates the expression of antimicrobials, cytokines and chemokines, thus helping to fight infections as well as recruiting the adaptive immune system. Although NFKB responds to a wide variety of signals, the processes in which stimulus-specificity is attained are still unclear. Here, we characterized the response of one of the NFKB members, RELA, to five stimuli mimicking infection in nasopharyngeal epithelial cells. When comparing RELA genome-wide binding sites , we detected most of them to be overlapping among the different stimulations. Yet, we distinguished a minority of stimulus-specific RELA binding sites. Interestingly, some of these seemed to have a biological effect as they correlated with corresponding gene expression. Specifically, the response to Poly I:C mimicking viral dsRNA gave a distinct RELA profile binding the vicinity of antiviral genes. This group of binding sites was also enriched in Interferon Regulatory Factor motifs indicating that the interaction with more specialized TFs could contribute to stimulus-specific RELA activity. Furthermore, motif analysis revealed differences in the sequence of the NFKB motifs between certain stimulus-specific sets of peaks suggesting preferences for particular NFKB dimers in response to defined signals.
2018-01-30 | GSE91018 | GEO
Project description:Proteasome-mediated degradation of chromatin-bound NF-κB is critical in terminating the transcription of pro-inflammatory genes and can be triggered by Set9-mediated lysine methylation of RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we identified two structurally similar WD-40 repeat (WDR) proteins, WSB1 and WSB2, as the E3s that recognize chromatin-bound methylated RelA for polyubiquitination and proteasomal degradation. WSB1/2 specifically recognized methylated lysines (K) 314 and 315 of RelA via their WDR domains. Deletion of WRD in WSB1/2 or mutation of K314/315 of RelA to arginines abolished the interaction between WSB1/2 and RelA. RNA-sequencing of TNF--stimulated WSB1/2 knockdown cells revealed that WSB1/2 negatively regulated a subset of NF-B target genes with reduced polyubiquitination of chromatin-bound RelA. TNF- stimulated the methylation of RelA and the subsequent recruitment of WSB1/2 to the promoters of these NF-B target genes to terminate the transcription. Computational modeling demonstrated that a highly conserved Asp within repeat 3 of WDR domains of WSB1/2 coordinated its interaction with K314/K315 of RelA, with a higher pKa when either of the lysines is methylated. Together, these findings identify novel E3 ligases that target chromatin-bound methylated RelA for proteolysis to prevent sustained NF-κB activation, providing new targets for therapeutic intervention of NF-κB-mediated inflammatory diseases.
2024-05-29 | GSE233286 | GEO
Project description:The canonical NF-kB module induces nuclear translocation of RelA heterodimers from the latent cytoplasmic complexes. RelA directs inflammatory immune responses against microbial entities. However, aberrant RelA activity also triggers destructive inflammation, including those associated with inflammatory bowel disease (IBD). What provokes this pathological RelA activity remains unclear. As such, the noncanonical NF-kB pathway activates RelB heterodimers and mediates immune organogenesis. Because NF-kB-activating pathways are interlinked, we asked if noncanonical NF-kB signaling exacerbated intestinal inflammation. Our investigation revealed recurrent engagement of the noncanonical pathway in human IBD. In a mouse model of chemical colitis, the noncanonical NF-kB signaling gene Nfkb2 aggravated inflammation by amplifying the RelA activity induced in intestinal epithelial cells. Our mechanistic studies clarified that noncanonical signaling augmented the abundance of latent RelA complexes leading to hyperactive canonical NF-kB response in the colitogenic gut. In sum, latent dimer homeostasis appears to link noncanonical NF-kB signaling to RelA-driven inflammatory pathologies.
2021-07-07 | GSE148577 | GEO
Project description:Phosphorylation of the RelA(p65) Thr505 residue by Chk1 provides a mechanism of crosstalk between NF-kappaB signalling and DNA replication stress 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 a variety of aberrant responses to stress. Following partial hepatectomy, livers from RelA T505A mice proliferate more rapidly. Moreover, in the Emu-Myc B-cell lymphoma model, tumorigenesis is more rapid and mice succumb to disease at significantly earlier times. Analysis of embryonic fibroblasts from RelA T505A mice challenged with a range of DNA damaging agents revealed loss of pro-apoptotic RelA functions, at least in part due to DUSP1 dependent regulation of p38 MAP kinase activity. This data reveals a critical pathway controlling NF-kappaB function that acts to suppress tumour-promoting activities of RelA.
2015-11-30 | E-MTAB-2686 | biostudies-arrayexpress
Project description:Developmental signals are known to modulate inflammation. How ever, the mechanistic insight that links developmental and inflammatory signaling remains elusive. In the current study, we identifya critical role of NF-kB system in mediating stimulus specific crosstalk that allows developmental LTbR signals to sustain inflammatory TLR4 induced RelA/NF-kB response and gene expression. LTbR activated non-canonical signaling targets canonical TLR4 induced, nfkb2 encoded p100 not only to deplete inhibitory IkBd/(p100)2, but also to supplement RelA:p52/NF-kB dimers. Robust crosstalk in the gut epithelial cells are important, as crosstalk-defective nfkb2-/- mice succumbed to gut infection by Citrobacter rodentium due to hypo-inflammatory responses. Finally, we present evidence for a crosstalk motif that integrates tissue microenvironment derived developmental cues to ameliorate the pathogen response. Total RNA from WT early passage MEFs stimulated with ligands LPS, LTbR and LPS+LTbR for 24hrs were analyzed for global gene expression levels
2015-05-01 | E-GEOD-62301 | biostudies-arrayexpress
Project description:Developmental signals are known to modulate inflammation. How ever, the mechanistic insight that links developmental and inflammatory signaling remains elusive. In the current study, we identifya critical role of NF-kB system in mediating stimulus specific crosstalk that allows developmental LTbR signals to sustain inflammatory TLR4 induced RelA/NF-kB response and gene expression. LTbR activated non-canonical signaling targets canonical TLR4 induced, nfkb2 encoded p100 not only to deplete inhibitory IkBd/(p100)2, but also to supplement RelA:p52/NF-kB dimers. Robust crosstalk in the gut epithelial cells are important, as crosstalk-defective nfkb2-/- mice succumbed to gut infection by Citrobacter rodentium due to hypo-inflammatory responses. Finally, we present evidence for a crosstalk motif that integrates tissue microenvironment derived developmental cues to ameliorate the pathogen response.
2015-05-01 | GSE62301 | GEO