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Selective Regulation of a Defined Subset of Inflammatory and Immunoregulatory Genes by an NF-kB p50-IkBz Pathway

ABSTRACT: The five NF-kB family members and three nuclear IkB proteins play diverse biological roles, but the mechanisms by which distinct NF-kB and NF-kB:IkB complexes contribute to selective gene transcription remain poorly understood. Using nascent transcript RNA-seq, we observed considerable overlap between p50-dependent and IkBz-dependent genes in Toll-like receptor 4 (TLR4)-activated macrophages. Key inflammatory and immunoregulatory genes, including Il6, Il1b, Nos2, Lcn2, and Batf, were among the p50-IkBz co-dependent genes. IkBz typically bound genomic sites occupied earlier by NF-kB dimers. However, p50-IkBz co-dependence did not coincide with the preferential binding of either protein, as p50, IkBz, and RelA co-occupied thousands of sites. A common feature of p50-IkBz co-dependent genes was close proximity to a p50/RelA/IkBz co-bound site exhibiting p50-dependent binding of RelA and IkBz. This result and others suggest that IkBz function is not restricted to p50 homodimers. Notably, IkBz and the p50-IkBz target genes comprise a high percentage of genes that exhibited the greatest differential expression between TLR4-stimulated and tumor necrosis factor receptor (TNFR)-stimulated macrophages, with ectopic IkBz rescuing a subset of these genes. These results reveal a defined p50-IkBz pathway that selectively activates a set of key inflammatory and immunoregulatory genes and serves as an important contributor to the differential responses to TNFR and TLR4.

ORGANISM(S): Mus musculus

PROVIDER: GSE249261 | GEO | 2024/03/14

REPOSITORIES: GEO

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Selective Regulation of a Defined Subset of Inflammatory and Immunoregulatory Genes by an NF-kB p50-IkBz Pathway

Project description:The five NF-kB family members and three nuclear IkB proteins play diverse biological roles, but the mechanisms by which distinct NF-kB and NF-kB: IkB complexes contribute to selective gene transcription remain poorly understood. Using nascent transcript RNA-seq, we observed considerable overlap between p50-dependent and IkBz-dependent genes in Toll-like receptor 4 (TLR4)-activated macrophages. Key inflammatory and immunoregulatory genes, including Il6, Il1b, Nos2, Lcn2, and Batf, were among the p50-IkBz co-dependent genes. IkBz typically bound genomic sites occupied earlier by NF-kB dimers. However, p50-IkBz co-dependence did not coincide with preferential binding of either protein, as p50, IkBz, and RelA co-occupied thousands of sites. A common feature of p50-IkBz co-dependent genes was close proximity to a p50/RelA/IkBz co-bound site exhibiting p50-dependent binding of RelA and IkBz. This result and others suggest that IkBz function is not restricted to p50 homodimers. Notably, IkBz and the p50-IkBz target genes comprise a high percentage of genes that exhibited the greatest differential expression between TLR4-stimulated and tumor necrosis factor receptor (TNFR)-stimulated macrophages, with ectopic IkBz rescuing a subset of these genes. These results reveal a defined p50-IkBz pathway that selectively activates a set of key inflammatory and immunoregulatory genes and serves as an important contributor to the differential responses to TNFR and TLR4.

2024-04-23 | GSE245681 | GEO

Immune differentiation regulator p100 tunes NF-kB responses to TNF

Project description:Stringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-kB pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-kB system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including IkBa, thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-kB pathway controls a separate RelB activity associated with immune differentiation. In a systems modeling approach, we uncovered an unexpected role of p100, a constituent of the noncanonical pathway, in TNF signaling. Brief TNF stimulation of p100-deficient cells produced an additional late NF-kB activity composed of the RelB:p50 heterodimer, which distorted the TNF-induced gene-expression program. Periodic TNF pulses augmented this RelB:p50 activity, which was reinforced by NF-kB-dependent RelB synthesis. In sum, the NF-kB system seems to engage distantly related molecular species for enforcing dynamical and gene controls of immune-activating TNF signaling.

2020-08-22 | GSE119961 | GEO

AhmedMobeen2021 - NF-kB Activation Model

Project description:NF-kappaB Activation Model includes the activation of both NFKB1:RELA and NFKB2:RELB for Canonical and Non-Canonical Pathway respectively. The model includes the pathway model integrated with post-translational modifications of NF-kB subunits that regulate the NFKB1:RELA and NFKB2:RELB activity. The processes that are regulated by NF-kB pathway can be monitored through following readouts NFKB1:RELA Activity, NFKB2:RELB Activity, Degraded RelA, Degraded RelB, Degraded IkB, Degraded NIK, Apoptosis, Tumour, Antiviral Activity, B Cell Growth and Cell Migration. However, last 5 processes above are also influenced by other pathways too, therefore while making predictions, caution has to be exercised.

2022-05-27 | MODEL2001290001 | BioModels

The NF-kB genomic landscape in lymphoblastoid B-cells

Project description:The nuclear factor kB (NF-kB) subunits RelA, RelB, c-Rel, p50 and p52 are each critical for B-cell development and function. To systematically characterize their responses to canonical and non-canonical NF-kB pathways activity, we performed ChIP-seq analysis in lymphoblastoid B-cells. We found a surprisingly complex NF-kB binding landscape, which did not readily reflect the two NF-kB pathway paradigm. Instead, ten subunit binding patterns were observed at promoters and eleven at enhancers. Surprisingly, nearly one-third of NF-kB binding sites lacked kB motifs. De novo motif finding uncovered distinct modes of NF-kB recruitment at these sites. The oncogenic forkhead box protein FOXM1 and NF-kB co-occupied many kB sites despite the absence of a FOXM1 DNA motif. FoxM1 knockdown decreased expression of key NF-kB targets and caused apoptosis. Our study highlights opportunities for selective therapeutic NF-kB blockade. ChIP-seq was used to define the genomic landscape of NF-kB DNA binding in lymphoblastoid cells.

2014-08-29 | E-GEOD-55105 | biostudies-arrayexpress

The NF-kB genomic landscape in lymphoblastoid B-cells

2014-08-29 | GSE55105 | GEO

Transcription of Tnfaip3 is regulated by NF-kB and p38 via C/EBPβ in activated macrophages

Project description:Macrophages play a pivotal role in the immune system through recognition and elimination of microbial pathogens. Toll-like receptors (TLRs) on macrophages interact with microbial substances and initiate signal transduction through intracellular adapters. TLR4, which is important for the response to lipopolysaccharide (LPS), triggers downstream signaling mediators and eventually activates IkB kinase (IKK) complex and mitogen-activated protein kinases (MAPKs) such as p38. Previous reports revealed that, in addition to NF-kB, the induction of some LPS-inducible genes in macrophages required another transcription factor whose activity depends on p38. However, these transcription factors remained to be identified. Among these genes, NF-kB and C/EBPβ, a p38 downstream transcription factor, were predicted to co-regulate genes in LPS-stimulated BMDMs. Based on the subsequent results of a chromatin immunoprecipitation assay, we demonstrated that Tnfaip3 is regulated by both NF-kB and p38-dependent C/EBPβ. These results elucidate our understanding of the tight regulation of innate immunity. In order to identify p38-activated transcription factors that cooperate with NF-kB in response to LPS stimulation, microarrays were used to identify genes regulated by both NF-kB and p38 using wild-type, IKK-depleted, and p38 inhibitor-treated mouse bone marrow-derived macrophages (BMDMs). In silico analysis of transcription factor binding sites was used to predict the potential synergistic transcription factors from the co-expressed genes.

2015-04-28 | E-GEOD-46361 | biostudies-arrayexpress

Developmental LTbR synergistically activates TLR4 mediated inflammatory RelA/NF-kB response

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

TNF-induced gene-expressions in Nfkb2-/- MEFs and its derivatives

Project description:As such, TNF triggers the canonical NF-?B pathway to induce a nuclear NF-?B activity composed of the RelA:p50 dimer in WT cells. Nfkb2 encodes p100, which regulates the activity of the RelB NF-?B heterodimers during immune cell-differentiation via the noncanonical pathway. Our biochemical analyses revealed that an absence of p100 instead repositions RelB under the control of the TNF-activated canonical pathway. Indeed, chronic TNF treatment of Nfkb2-/- cells activates the RelA:p50 dimer and an additional RelB:p50 dimer. On the other hand, TNF stimulation of Relb-/-Nfkb2-/- and Rela-/-Nfkb2-/- MEFs exclusively activated the RelA:p50 dimer and the RelB:p50 dimer, respectively. We treated this panel of knockout MEFs with TNF for 6h before being subjected to microarray mRNA analysis. We also included in our analysis WT MEFs and Rela-/-Relb-/-Rel-/- MEFs, which served as a negative control. Our analyses revealed overlapping and distinct gene-expression specificities of RelA:p50 and RelB:p50 dimers activated in mutant cells in response to TNF.

2019-06-13 | GSE99980 | GEO

Transcription of Tnfaip3 is regulated by NF-kB and p38 via C/EBPβ in activated macrophages

2015-04-28 | GSE46361 | GEO

An EZH2-NF-kB Regulatory Axis Drives Expression of Pro-Oncogenic Genetic Signatures in TNBC

Project description:EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Paradoxically, accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting gene expression in triple negative breast cancer (TNBC) cells through interactions with the transcription factor NF-kB. We define a genomic profile of EZH2 and NF-kB factor RelA, RelB, and NFKB2/p52 co-localization and positive regulation of a subset of NF-kB targets and genes associated with oncogenic functions in TNBC, which is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified EZH2 transactivation domain (TAD), which mediates EZH2 recruitment to and activation of certain NF-kB-dependent genes, and supports downstream stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-kB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-kB-dependent regulatory mechanisms.

2023-07-10 | GSE223959 | GEO

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