C-Rel gain in B cells dose-dependently drives germinal center reactions and autoantibody production in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA599120 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10832000.fastq.gz | Fastqsanger.gz | |||
| SRR10832001.fastq.gz | Fastqsanger.gz | |||
| SRR10832002.fastq.gz | Fastqsanger.gz | |||
| SRR10832003.fastq.gz | Fastqsanger.gz | |||
| SRR10832004.fastq.gz | Fastqsanger.gz |
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Project description:Single nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpress c- Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictate expansion of germinal center (GC) B cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescues terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GC B cells transcription-independent regulation produces the highest c-Rel protein levels amongst B cell subsets. In c-Rel overexpressing GC B cells this causes enhanced nuclear translocation, a profoundly altered transcriptional program and increased proliferation. Finally, we provide the first link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells causes autoantibody production and renal immune complex deposition.
2020-06-04 | GSE143156 | GEO
Project description:Single-nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center B (GCB) cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels among B cell subsets. In c-Rel-overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program, and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.
| S-EPMC7260018 | biostudies-literature
Project description:Rel and RelA proteins were stably expressed in the chicken DT40 pre-B cell line and analyzed by transcription profiling to identify transformation-impacting genes regulated by NF-kB’s oncogenic v-Rel and c-Rel proteins. This analysis uncovered both common and differential gene expression profiles in cells expressing Rel vs. RelA proteins, and revealed that Rel protein expression can lead to gene-specific transcriptional repression, as seen for key B-cell receptor (BCR) components and signaling molecules like B-cell linker (BLNK), the B-cell adaptor for PI3K (BCAP) and Igλ. These were also downregulated in cells expressing a transformation-competent chimeric RelA/v-Rel protein, suggesting a correlation with the capacity of Rel proteins to transform lymphocytes. DNA binding, ChIP and transformation assays indicate that downregulation of BLNK and BCAP is an important contributing factor to the malignant transformation of lymphocytes by Rel and suggest that gene repression may be as important as transcriptional activation for the transforming activity of Rel proteins. Keywords: Comparative transcriptional profiling
2008-02-14 | GSE9544 | GEO
Project description:To further understand the role of c-Rel in fibrogensis, label-free mass spectrometric analysis was performed on the secretome of cultured WT and Rel-/- M0, M1 and M2 polarised macrophages as well as control and TGFB1-stimulated hepatocytes.
2020-09-28 | PXD017320 | Pride
Project description:Gallus gallus breed:REL Genome sequencing
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Project description:This SuperSeries is composed of the following subset Series: GSE37664: Human cerebrospinal fluid autoantibody lipid microarray profiling (Fig. 1A) GSE37670: Human cerebrospinal fluid autoantibody lipid microarray profiling (Fig. 2A) GSE37826: Human cerebrospinal fluid autoantibody lipid microarray profiling (Fig. 2C) Refer to individual Series
2012-05-08 | E-GEOD-37830 | biostudies-arrayexpress
Project description:'The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour promoting transcription factor. Here we report the surprising result that c-rel -/- mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the Eμ-Myc lymphoma cells but, counter-intuitively, c-rel -/- Eμ-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c-Rel led to earlier onset of disease, microarray gene expression analysis was performed on B-cells from 4-week old, wild type and c-rel -/- Eμ-Myc mice. Extensive changes in gene expression were not seen at this age but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Q-PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant Eμ-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover Bach2 expression was also downregulated in c-rel -/- TCL1-Tg mice and RelA Thr505Ala mutant Eμ-Myc mice. Analysis of wild type Eμ-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel-/- mice. Confirming the relevance of these findings to human disease, analysis of ChIP-Seq data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B-cells, while treatment of Burkitt''s lymphoma cells with inhibitors of the NF-κB/IKK pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. This data reveals a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context dependent complexity of NF-κB signalling in cancer.'
2014-12-31 | E-MTAB-2774 | biostudies-arrayexpress
Project description:Adaptive immunity and the five vertebrate NF-kB/Rel family members first appeared in cartilaginous fish, suggesting that NF-kB family expansion allowed the acquisition of new functions to regulate adaptive immune responses. Transcriptome profiling revealed that, even in macrophages, the NF-kB family member, c-Rel, most potently regulates a cytokine gene linked to adaptive immunity, Il12b, with limiting roles at key regulators of innate immunity. Neofunctionalization of c-Rel to regulate Il12b depends on its unique DNA-binding properties, which we examined using structural, biochemical, functional, and genomic approaches. Among our findings was functional c-Rel homodimer binding to motifs with little resemblance to canonical NF-kB motifs. To determine whether c-Rel’s unique binding properties drove c-Rel-RelA divergence, we compared binding properties in various vertebrate species. c-Rel-RelA binding properties diverged in mammals and amphibians but were comparable in earlier vertebrates, suggesting that divergent DNA binding emerged relatively late during vertebrate evolution to support increasing complexity of adaptive immune regulation.
2024-03-11 | GSE243011 | GEO
Project description:Adaptive immunity and the five vertebrate NF-kB/Rel family members first appeared in cartilaginous fish, suggesting that NF-kB family expansion allowed the acquisition of new functions to regulate adaptive immune responses. Transcriptome profiling revealed that, even in macrophages, the NF-kB family member, c-Rel, most potently regulates a cytokine gene linked to adaptive immunity, Il12b, with limiting roles at key regulators of innate immunity. Neofunctionalization of c-Rel to regulate Il12b depends on its unique DNA-binding properties, which we examined using structural, biochemical, functional, and genomic approaches. Among our findings was functional c-Rel homodimer binding to motifs with little resemblance to canonical NF-kB motifs. To determine whether c-Rel’s unique binding properties drove c-Rel-RelA divergence, we compared binding properties in various vertebrate species. c-Rel-RelA binding properties diverged in mammals and amphibians but were comparable in earlier vertebrates, suggesting that divergent DNA binding emerged relatively late during vertebrate evolution to support increasing complexity of adaptive immune regulation.
2023-11-29 | GSE243010 | GEO
Project description:The expression array data will be merged with Rel-B ChIP-Seq data in HL cell lines. This will show REL-B direct and indirect controlled downstream target genes HL cells were infected with a retrovirus that delivers a specific shRNA sequence to knock down the expression of REL-B
2012-01-20 | E-GEOD-35224 | biostudies-arrayexpress