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C-Rel gain in B cells dose-dependently drives germinal center reactions and autoantibody production in mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE143156 | GEO | 2020/06/04

REPOSITORIES: GEO

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c-Rel gain in B cells dose-dependently drives germinal center reactions and autoantibody production in mice

Project description:c-Rel gain in B cells dose-dependently drives germinal center reactions and autoantibody production in mice

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Positive and negative regulation of lymphomagenesis by the NF-kappaB subunit c-Rel

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

c-Rel gain in B cells drives germinal center reactions and autoantibody production.

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.

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Transcriptional profiling of NF-kB's Rel and RelA proteins

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

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Gene expression profiling of Hodgkin Lymphoma cell line following REL-B depletion

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

c-Rel-dependent monocytes are potent immune suppressor cells in cancer

Project description:Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of leukocytes that are important for tumorigenesis and tumor immunotherapy. They comprise up to 10% of leukocytes in the blood of tumor patients and their depletion may be required for successful tumor immunotherapy. However, the identity of MDSCs remains obscure, primarily due to their heterogeneity and lack of a known lineage-specific transcription factor specifying their differentiation. Using single-cell transcriptomics and gene knockout approaches, we now describe a subset of murine and human myeloid suppressor cells, named rel-dependent monocytes (rMos), which are programmed by the transcription factor c-Rel of the NF-B family. Unlike MDSCs described previously, the c-Rel-dependent monocytes expressed a high amount of the proinflammatory cytokine IL-1β together with a low level of suppressive molecule arginase 1. Both in vitro and in tumor-bearing mice, these c-Rel+IL-1βhiArg1 monocytes promoted tumor growth by potently suppressing T cell function and showed a strong migratory phenotype, all of which were impaired by c-Rel deficiency or inhibition. Mechanistic studies revealed that c-Rel controlled the expression of monocyte signature genes through a unique transcriptional complex called the c-Rel enhanceosome, and IL-1CCL2 crosstalk between tumor cells and the rel-dependent monocytes maintained the suppressive tumor microenvironment. Thus, c-Rel specifies the development of a suppressive monocyte population and could be selectively targeted for treating cancer.

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Identification of c-Rel and RelA binding regions in stimulated EL4 cells

Project description:c-Rel and RelA are members of the NF-kappaB family of transcription factors. They both have important roles in T cell activation. To discover where in the genome c-Rel and RelA bind and hence which genes they may directly target, we used ChIP-chip with EL4 cells stimulated with phorbol ester (PMA) and Ionomycin. We have identified regions in EL4 cells (background strain: C57BL/6N) activated for 2h or 8h by PMA and Ionomycin, that bind the transcription factors c-Rel and RelA. Immunoprecipitated samples from EL4 cells stimulated with PMA and ionomycin for 2 h and 8 h with antibodies against RelA or c-Rel respectively were used for ChIP-on-chip experiments. In addition, samples from total input and mock immunoprecipitation were used as controls. Biological triplicates were used.

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