NF-kB regulator Bcl3 modulates bone density and turnover
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA515412 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8447210_1.fastq.gz | Fastqsanger.gz | |||
| SRR8447210_2.fastq.gz | Fastqsanger.gz | |||
| SRR8447211_1.fastq.gz | Fastqsanger.gz | |||
| SRR8447211_2.fastq.gz | Fastqsanger.gz | |||
| SRR8447212_1.fastq.gz | Fastqsanger.gz |
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Project description:B-cell lymphoma 3-encoded protein (Bcl3) is an intimate and context-specific regulator of the NF-kB family of transcription factors, a ubiquitous master regulator involved in many homeostatic and inflammatory processes. NF‑kB signalling determines the fates of bone-forming osteoblasts and bone-resorbing osteoclasts. Herein we show that Bcl3 is a negative regulator of NF‑kB via control of osteoblast and osteoclast function. Mice lacking Bcl3 (Bcl3−/−) have congenitally increased bone density, long bone dwarfism, increased biomechanical strength and altered bone turnover. Bcl3−/− osteoblasts and osteoclasts have accelerated differentiation and increased activity; whereas, rescue overexpression with a Bcl3 mimetic peptide inhibits differentiation. Early-differentiating Bcl3−/− osteoblasts have altered gene transcription favouring bone formation, including perturbation of the RANKL-OPG axis. In a model of osteoarthritic aberrant mineralisation Bcl3−/− mice exhibit decreased pathological osteophyte formation. Cumulatively, these findings identify Bcl3 as a viable target for controlling NF‑kB signalling in the treatment of skeletal pathologies.
2019-01-17 | GSE125153 | GEO
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
Project description:To address the role of NF-kB in aging in vivo, we utilized a well-characterized system that allows inducible and site-specific inhibition of NF-kB activity in murine skin. The hormone binding domain of the mutant estrogen receptor that is responsive to 4-hydroxytamoxifen (4-OHT) was fused to a mutant of p50 (IDNkB, inducible dominant negative NF-kB) that dimerizes with other NF-kB subunits but is unable to bind DNA, thus dominantly inhibiting NF-kB activity. Expression was driven within the basal layer of murine epidermis by the keratin 14 promoter in transgenic mice. To test whether NF-kB activity is required to maintain age-associated gene expression, we applied topical 4-OHT and ethanol vehicle (EtOH) for two weeks to the right (R) and left (L) dorsal flanks, respectively, of chronologically aged transgenic mice (O, 18-23 months). Young transgenic mice (Y, 1 month) were treated in parallel as control. Skin samples were harvested and analyzed for gene expression using mouse cDNA microarrays containing 35,217 elements, representing 18,880 unique genes. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set Computed
2010-06-30 | E-GEOD-3845 | biostudies-arrayexpress
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.
2014-08-29 | GSE55105 | GEO
Project description:Abstract. Deregulated c-MYC is found in a variety of cancers where it promotes proliferation as well as apoptosis. In many hematological malignancies enhanced NF-kB exerts prosurvival functions. Here we investigated the role of NF-kB in mouse and human c-MYC-transformed lymphomas. The NF-kB-pathway is extinguished in murine lymphoma cells and extrinsic stimuli typically inducing NF-kB activity fail to activate this pathway. Genetic activation of the NF-kB pathway induces apoptosis in these cells, while inhibition of NF-kB by an IkBa superrepressor provides a selective advantage in vivo. Furthermore, in human Burkitt´s lymphoma cells we find that NF-kB activation induces apoptosis. NF-kB upregulates Fas and predisposes to Fas-induced cell death, which is caspase 8 mediated and can be prevented by CFLAR overexpression. We conclude that c-MYC overexpression sensitizes cells to NF-kB-induced apoptosis and persistent inacvtivity of NF-kB signaling is a prerequisite for MYC-mediated tumorigenesis. We could also show that low immunogenicity and Fas insensitivity of MYC driven lymphoma cells is reversed by activation of NF-kB. Our observations provide a molecular explanation for the described absence of the NF-kB signaling in Burkitt´s lymphoma and question the applicability of NF-kB inhibitors as candidates for treatment of this cancer.
2009-07-22 | GSE17129 | GEO
Project description:To address the role of NF-kB in aging in vivo, we utilized a well-characterized system that allows inducible and site-specific inhibition of NF-kB activity in murine skin. The hormone binding domain of the mutant estrogen receptor that is responsive to 4-hydroxytamoxifen (4-OHT) was fused to a mutant of p50 (IDNkB, inducible dominant negative NF-kB) that dimerizes with other NF-kB subunits but is unable to bind DNA, thus dominantly inhibiting NF-kB activity. Expression was driven within the basal layer of murine epidermis by the keratin 14 promoter in transgenic mice. To test whether NF-kB activity is required to maintain age-associated gene expression, we applied topical 4-OHT and ethanol vehicle (EtOH) for two weeks to the right (R) and left (L) dorsal flanks, respectively, of chronologically aged transgenic mice (O, 18-23 months). Young transgenic mice (Y, 1 month) were treated in parallel as control. Skin samples were harvested and analyzed for gene expression using mouse cDNA microarrays containing 35,217 elements, representing 18,880 unique genes. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2007-12-01 | GSE3845 | GEO
Project description:2 This project is to identify the potential neddylation sites in human NF-kB inducing kinase (A.k.a. Map3K14). NIK-HA or NIK-HA in combination with FLAG-NEDD8 were co-expressed in HEK293T cells. NIK-HA were pulled down via denaturing immunoprecipitation protocol, subject to SDS-PAGE, in-gel trypsin digestion, and Nano LC-MS/MS Analysis. The potential peptides containing K-GG sites were identified.
2023-03-10 | PXD038653 | Pride
Project description:The ability of dendritic cells (DC) to initiate immunity and induce antigen-specific tolerance makes DC ideal targets for pharmacological intervention into immune responses. NF-kB factors are a family of transcriptional regulators important for DC development and function. However, the identity of NF-kB target genes that are central to DC biology is largely unknown. In the present study IkBa super repressor (IkBa-SR) and DNA microarray analysis were used to determine the repertoire of NF-kB responsive genes in DC. In DC these genes regulate vital DC functions of antigen uptake and presentation, motility, survival, etc. Taking in account limitations of the genome-wide microarray analysis, generated transcription factor data were confirmed by the independent means of RT-PCR and chromatin immunoprecipitation. Kinetics of NF-kB induction by well-known DC activatory agents TNFa and LPS were further analysed. NF-kB regulated genes can be potentially useful targets for the development of more specific anti-inflammatory agents for clinical applications. Keywords: drug treatment, adenovirus transduction
2012-12-31 | GSE8009 | GEO
Project description:By binding to specific DNA elements, known collectively as “κB sites”, contained within the promoters/enhancers of target genes, NF-κB regulates gene expression. We found that the identity of the central base pair (bp) of κB sites profoundly impacts the transcriptional activity of NF-κB dimers. RelA dimers prefer an A/T bp at this position for optimum transcriptional activation (A/T-centric) and discriminate against G/C-centric κB sites. The p52 homodimer, in contrast, activates transcription from G/C-centric κB sites in complex with Bcl3 but represses transcription from the A/T-centric sites. The p52:Bcl3 complex binds to these two classes of κB sites in distinct modes permitting recruitment of coactivator, corepressor, or both coactivator and corepressor complexes in promoters containing G/C, A/T or both G/C and A/T-centric sites. Therefore, through sensing of bp differences within κB sites, NF-κB dimers modulate biological programs by activating, repressing and altering expression of effector genes. Total RNA extracted from bone marrow derived macrophages (BMDMs) with Bcl3 siRNA knockdown or mouse scramble siRNA knockdown were subjected to LPS stimulation.
2012-08-06 | E-GEOD-39922 | biostudies-arrayexpress