The Xbp1-regulated transcription factor Mist1 restricts antibody secretion by restraining Blimp1 expression in plasma cells
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ABSTRACT:
PROVIDER: PRJNA787613 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17183557.fastq.gz | Fastqsanger.gz | |||
| SRR17183558.fastq.gz | Fastqsanger.gz | |||
| SRR17183559.fastq.gz | Fastqsanger.gz | |||
| SRR17183560.fastq.gz | Fastqsanger.gz | |||
| SRR17183565.fastq.gz | Fastqsanger.gz |
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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
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
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.
2016-01-18 | GSE70981 | GEO
Project description:Although early developmental processes involve cell fate decisions that define the body axes and establish progenitor cell pools, development does not cease once cells are specified. Instead, most cells undergo specific maturation events where changes in the cell transcriptome ensure that the proper gene products are expressed to carry out unique physiological functions. Pancreatic acinar cells mature post-natally to handle an extensive protein synthetic load, establsih organized apical-basal polarity for zymogen granule trafficking, and assemble gap-junctions to perimt efficient cell-cell communication. Despite significant progress in defining transcriptional networks that control initial acinar cell specification and differentiation decisions, little is know regarding the role of transcription factors in the specification and maintenance of maturation events. One candidate maturation effector is MIST1, a secretory cell-restricted transcription factor that has been implicated in controlling regulated exocytosis events in a number of cell types. Embryonic knock-out of MIST1 generates acinar cells that fail to establish an apical-basal organization, fail to properly localize zymogen granule and fail to communicate intra-cellularly, making the exocrine organ highly suceptible to pancreatic diseases. In an effort to identify the gene expression differences responsible for MIST1 regulating mature acinar properties. We generated a tamoxifen-inducible mouse model where MIST1 expression could be activated in vivoand performed gene expression arrays on wildtype, MIST1-null, and induced MIST1 pancreatic RNA. RNA was isolated from pancreata of 8 week old mice using the Qiagen RNeasy Midi kit. Pancreta of wildtype, MIST1-null, and MIST1-null with a tamoxifen inducible MIST1-expressing transgene were harvested 36 hours post-tamoxifen administration. Therefore, this experiment provides information on steady-state gene expression differences between wildtype and MIST1-null mice as well as immediate gene expression changes induced by MIST1 expression.
2012-05-03 | E-GEOD-34232 | biostudies-arrayexpress
Project description:MIST1 over-expression has not been analyzed in a cell type that does not express endogenous MIST1. Here, we force-express ectopic MIST1 in the hepatocytes of mouse livers. We extracted mRNA and compared gene expression levels between MIST1-expressing mouse livers to controls.
2017-01-14 | GSE93612 | GEO
Project description:Mist1+ cells and parietal cells in mouse stomach were separatedly sorted, and RNAs were isolated. Mist1 (also known as Bhlha15) is expressed in gastric chief cells and gastric stem cells in mice. However, more specific genes for each population needs to be identified to better understand the precise biology in these cell populations. In order to address cell specific gene signature, we separately sorted Mist1+ gastric chief cells and Mist1+ gastric stem cells by FACS, and performed microarray analysis. Mist1+ gastric chief cells were sorted by using Mist1-CreERT; R26-TdTomato mouse stomach, immediately after tamoxifen administration. Mist1+ gastric stem cells were sorted by chief cell-ablated Mist1-CreERT; R26-TdTomato mouse stomach, combining with Lgr5-DTR mice. Lgr5-expressing chief cells were ablated by giving DT into these mice. As a control, acid-secreting gastric parietal cell samples were used. Mice were treated with or without Lgr5-DT ablation before sorting.
2019-06-25 | GSE133205 | GEO
Project description:MIST1 over-expression has not been analyzed in a cell type that does not express endogenous MIST1. Here, we force-express ectopic MIST1 in the parietal cells of mouse stomachs. We extracted whole corpus stomach mRNA and compared gene expression levels between MIST1-expressing mouse stomachs to controls.
2016-11-01 | GSE81549 | GEO
Project description:Mist1+CD24hi cells and Mist1+CD24lo cells in mouse small intestine were separatedly sorted, and RNAs were isolated. Mice were treated with irradiation, Lgr5-DT ablation, doxorubicin, or NICD expression before sorting.
2018-03-17 | GSE111934 | GEO
Project description:Although early developmental processes involve cell fate decisions that define the body axes and establish progenitor cell pools, development does not cease once cells are specified. Instead, most cells undergo specific maturation events where changes in the cell transcriptome ensure that the proper gene products are expressed to carry out unique physiological functions. Pancreatic acinar cells mature post-natally to handle an extensive protein synthetic load, establsih organized apical-basal polarity for zymogen granule trafficking, and assemble gap-junctions to perimt efficient cell-cell communication. Despite significant progress in defining transcriptional networks that control initial acinar cell specification and differentiation decisions, little is know regarding the role of transcription factors in the specification and maintenance of maturation events. One candidate maturation effector is MIST1, a secretory cell-restricted transcription factor that has been implicated in controlling regulated exocytosis events in a number of cell types. Embryonic knock-out of MIST1 generates acinar cells that fail to establish an apical-basal organization, fail to properly localize zymogen granule and fail to communicate intra-cellularly, making the exocrine organ highly suceptible to pancreatic diseases. In an effort to identify the gene expression differences responsible for MIST1 regulating mature acinar properties. We generated a tamoxifen-inducible mouse model where MIST1 expression could be activated in vivoand performed gene expression arrays on wildtype, MIST1-null, and induced MIST1 pancreatic RNA.
2012-05-04 | GSE34232 | GEO
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