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Transcriptomic analysis of naïve B cells and plasma cells as well as in vitro stimulated B cells from Blimp1-GFP reporter mice [Blimp1_reporter_PC_stim]

ABSTRACT: Though it is known that plasma cells utilize the unfolded protein response to remodel their ER it is generally believed that this follows Blimp1-mediated transcriptional and translational increases in immunoglobulin protein. In this study we utilize Blimp1 reporter mice to examine the earliest activation of UPR-affiliated gene expression in plasma cell inductive stimulation of B cells. We combine in-vivo gene expression of follicular B cells, marginal zone B cells from spleen and short and long lived plasma cells from bone marrow with in-vivo generated activated B cells and plasma cells from the same mice to examine gene expression before and after Blimp1-upregulation. Using a novel in-vitro stimulation approach we separate those UPR-affiliated genes activated by B cell activation and those requiring a plasma cell inductive stimulus. We report here that these plasma cell specific UPR-affiliated genes are activated in absence of ER-stress prior to upregulation of Blimp1.

ORGANISM(S): Mus musculus

PROVIDER: GSE141419 | GEO | 2019/12/05

REPOSITORIES: GEO

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Transcriptomic analysis of in-vitro plasma cell generation from follicular B cells lacking Raptor [Raptor_PC_stim]

Project description:Early UPR-affiliated gene expression occurs before Blimp1 upregulation and independent of canonical ER-stress activated Xbp1. In linked companion studies we detailed how Xbp1-independent activation of early plasma cell specific UPR-affiliated gene expression occurs prior to Blimp1 upregulation. Having observed that these genes overlapped with canonical mTORC1 signature genes and that PC-poised marginal zone B cells have higher base line mTORC1 signaling we designed this experiment to assess the dependence of early ER-remodeling on mTORC1 signaling in plasma cell differentiation. To this end we mated mice harboring a floxed allele for the mTORC1 adapter Raptor (B6.Rptor-flox) to mice expressing a tamoxifen-inducible cre recombinase under the control of the human CD20 promoter (B6.hCD20-TamCre). These mice and their hCD20-TamCre-Rptor-wt litermates were fed oral tamoxifen in their diet for two weeks and follicular B cells were prepared for in-vitro plasma cell differentiation studies. We report here that as early as 24 hours of stimulation in culture we see a marked defect in the ability of Rptor null B cells to upregulate UPR-affiliated genes associated with plasma cell differentiation.

2019-12-05 | GSE141421 | GEO

Transcriptomic analysis of naïve B cells and antigen-specific activated B cells and plasma cells from 4dpi NP-LPS immunized mice [NPLPS_PC]

Project description:Little is known about the earliest transcriptomic events in plasma cell differentiation. Indeed, activation of UPR-affiliated gene expression is seen in in-vitro plasma cell differentiation prior to Blimp1 upregulation and in the absence of Xbp1 as we show in linked companion series. In this study, Blimp1 reporter mice were immunized with the T-independent antigen NP-LPS four days prior to spleen harvest and naïve B cells, NP-binding activated B cells and NP-binding plasma cells were analyzed by bulk RNA-seq. Here we report the activation of ER remodeling gene expression in antigen-specific activated B cells in-vivo prior to upregulation of Blimp1 transcription.

2019-12-05 | GSE141420 | GEO

Transcriptomic analysis of in-vitro plasma cell generation from follicular B cells lacking Xbp1 [Xbp1_PC_stim]

Project description:During plasma cell differentiation there is activation of UPR gene expression that has been termed the physiological UPR of plasma cell differentiation. This is canonically thought to be downstream of Blimp1-mediated increases in immunoglobulin gene production and activation of the Xbp1 transcription factor by the RNA splicing activity of the ER-stress sensor IRE1α. Having observed UPR-affiliated gene expression prior to upregulation of Blimp1 as reported in the companion linked series, we endeavored to determine the necessity of Xbp1 activity in the early remodeling of the ER in nascent plasma cells. To this end, we mated mice harboring a floxed exon 2 of the Xbp1 gene (Xbp1flox) to mice expressing a tamoxifen-inducible cre recombinase under the control of the human CD20 promoter (hCD20-TamCre). These mice and their hCD20-TamCre-Xbp1wt litermates were fed oral tamoxifen in their diet for two weeks and follicular B cells were prepared for in-vitro plasma cell differentiation studies. We report here that prior to plasma cell differentiation as measured by CD138 expression, which coincides temporally with Blimp1 expression, there is no defect in UPR-affiliated gene expression in cells lacking Xbp1.

2019-12-05 | GSE141422 | GEO

Blimp1 controls plasma cell physiology and function

Project description:Antibody-secreting plasma cells are the terminal stage of the B-cell lineage. Plasma cell differentiation requires a major resetting of gene expression to silence the B cell transcriptional program, whilst establishing secretory function and long-term survival. The transcription factors Blimp1 and Irf4 are essential for the initial differentiation of activated B cells to antibody-secreting cells, however their function in mature plasma cells remains elusive. We have found that while Irf4 was essential for plasma cell survival, Blimp1 was dispensable. Blimp1-deficient cells retained the unique plasma cell transcriptional signature, but lost the ability to secrete antibody or to maintain the characteristic size and ultrastructure of plasma cells. Blimp1 was required for full expression of many components of the unfolded protein response (UPR), including Xbp1 and Atf6, as well as for the appropriate processing of Igh mRNA. The overlap of Blimp1 and Xbp1 function was restricted to the UPR genes, with Blimp1 uniquely regulating activity of the mTOR pathway, plasma cell size and morphology. These studies establish Blimp1 as a major regulator of the UPR pathway that is also required for the unique metabolic requirements of plasma cells enabling the secretion of protective antibody. RNA-seq was performed on wild type, Blimp1-/- and Xbp1-/- mouse plasma cells. Between two to four biological replicates were generated and sequenced for each sample.

2016-01-18 | E-GEOD-70981 | biostudies-arrayexpress

An inter-chromosomal transcription hub activates the unfolded protein response in plasma cells

Project description:Previous studies have indicated that the transcription signature of antibody-secreting cells is closely associated with the induction of the unfolded protein response pathway (UPR). Here we have used genome-wide and single cell analyses to examine the folding patterns of plasma cell genomes. We found that plasma cells adopt a cartwheel configuration and undergo large-scale changes in chromatin folding at genomic regions associated with a plasma cell specific transcription signature. During plasma cell differentiation, Blimp1 assembles into an inter-chromosomal transcription hub with genes associated with the UPR, biosynthesis of the endoplasmic reticulum (ER) as well as a cluster of genes linked with Alzheimer’s disease. We suggest that the assembly of the Blimp1-UPR-ER transcription hub permits the coordinate activation of a wide spectrum of genes that collectively establish plasma cell identity.

2019-04-10 | GSE113014 | GEO

Blimp1 controls plasma cell physiology and function

2016-01-18 | GSE70981 | GEO

Transcription profiling of human cytokine induced A172 glioblastoma cells treated with erstressin and nostressin

Project description:The unfolded protein response (UPR), a signaling pathway triggered by endoplasmic reticulum (ER) stress, is induced by a range of environmental factors. Here we describe the identification and characterization of a synthetic small molecule, erstressin, which activates the UPR. Erstressin induced rapid phosphorylation of PERK and eIF2a and the alternative splicing of XBP-1, hallmark initiating events of the UPR. Further, erstressin activated the transcription of multiple genes involved in the UPR. Coincident with these effects, erstressin also downregulated the transcription of the inflammation-associated enzyme inducible nitric oxide synthase (iNOS) in cytokine-activated cells. A close analog of erstressin that failed to induce the UPR did not attenuate expression of iNOS, suggesting that both biological effects of erstressin were mediated by a common mechanism. Further, the structurally-distinct ER stressor thapsigargin also inhibited iNOS expression. Together these chemical genetic studies reveal an unanticipated anti-inflammatory role for the UPR. Experiment Overall Design: We utilized microarrays to understand the global effect of a novel compund, erstressin, on cytokine stimulated cells over time.

2008-06-15 | E-GEOD-7806 | biostudies-arrayexpress

Multifunctional role of the transcription factor Blimp1 in coordinating plasma cell differentiation

Project description:Blimp1 is an essential regulator of plasma cells. Here we studied its functions in early plasmablast differentiation by identifying regulated Blimp1 target genes. Blimp1 promoted plasmablast migration and adhesion by controlling many genes involved in these processes. It repressed several transcription factor genes and Aicda, thus silencing B-cell-specific gene expression, antigen presentation and class switch recombination in plasmablasts. It also directly activated genes, leading to increased expression of the plasma cell regulator IRF4 and proteins involved in immunoglobulin secretion. Blimp1 strongly induced immunoglobulin gene transcription by controlling the activity of Igh and Igk 3’ enhancers and regulated the posttranscriptional switch of expression from the membrane-bound to secreted immunoglobulin heavy-chain by activating Ell2. Notably, Blimp1 recruited chromatin-remodeling and histone-modifying complexes to regulate its target gene. Hence, many essential functions of plasma cells are under Blimp1 control.

2015-12-01 | GSE71698 | GEO

Precocious expression of Blimp1 in the B cell lineage causes autoimmunity

Project description:The transcription factor Blimp1 is not only an essential regulator of plasma cells, but also a risk factor for the development of autoimmune disease. Here, we demonstrate that the mouse Prdm1 (Blimp1) gene was partially activated at the chromatin and transcription level in early B cell development, although mature Prdm1 mRNA did not accumulate due to posttranscriptional regulation. By analyzing a mouse model that facilitated ectopic Blimp1 protein expression throughout B lymphopoiesis, we could demonstrate that Blimp1 impaired B cell development by interfering with the B cell gene expression program, while leading to an increased abundance of plasma cells by promoting premature plasmablast differentiation of immature and mature B cells. With progressive age, these mice developed an autoimmune phenotype characterized by the presence of autoantibodies and glomerulonephritis. Hence, these data identified ectopic Blimp1 expression as a novel mechanism that can explain how Blimp1 as a risk factor contributes to the development of autoimmune disease.

2018-11-30 | GSE111692 | GEO

The Xbp1-regulated transcription factor Mist1 restricts antibody secretion by restraining Blimp1 expression in plasma cells

Project description:Antibody secretion by plasma cells provides acute and long-term protection against pathogens. The high secretion potential of plasma cells depends on the unfolded protein response, which is controlled by the transcription factor Xbp1. Here, we analyzed the Xbp1-dependent gene expression program of plasma cells and identified Bhlha15 (Mist1) as the most strongly activated Xbp1 target gene. As Mist1 plays an important role in other secretory cell types, we analyzed in detail the phenotype of Mist1-deficient plasma cells in Cd23-Cre Bhlha15(fl/fl) mice under steady-state condition or upon NP-KLH immunization. Under both conditions, Mist1-deficient plasma cells were 1.4-fold reduced in number and exhibited increased IgM production and antibody secretion compared to control plasma cells. At the molecular level, Mist1 regulated a largely different set of target genes compared to Xbp1. Notably, expression of the Blimp1 protein, which is known to activate immunoglobulin gene expression and to contribute to antibody secretion, was 1.3-fold upregulated in Mist1-deficient plasma cells, which led to a moderate downregulation of most Blimp1-repressed target genes in the absence of Mist1. Importantly, a 2-fold reduction of Blimp1 (Prdm1) expression was sufficient to restore the cell number and antibody expression of plasma cells in Prdm1(Gfp/+) Cd23-Cre Bhlha15(fl/fl) mice to the same level seen in control mice. Together, these data indicate that Mist1 restricts antibody secretion by restraining Blimp1 expression, which likely contributes to the viability of plasma cells.

2022-10-18 | GSE190591 | GEO

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