Similar Datasets
Project description:The transcription factor IRF4 plays a critical role in plasma cell identity and function
| PRJNA523786 | ENA
Project description:Determine irf4 target genes in mouse B cells undergoing LPS differentiation to plasma cells in vitro. Determine targets of IRF4 by overexpression in a human GCB cell line. Keywords: cell type comparison design
2006-11-24 | GSE6337 | GEO
Project description:The transcription factor IRF4 regulates immunoglobulin class switch recombination and plasma cell differentiation. Its differing concentrations appear to regulate mutually antagonistic programs of B and plasma cell gene expression. We show IRF4 to be also required for generation of germinal center (GC) B cells. Its transient expression in vivo induced the expression of key GC genes including Bcl6 and Aicda. In contrast, sustained and higher concentrations of IRF4 promoted the generation of plasma cells while antagonizing the GC fate. IRF4 cobound with the transcription factors PU.1 or BATF to Ets or AP-1 composite motifs, associated with genes involved in B cell activation and the GC response. At higher concentrations, IRF4 binding shifted to interferon sequence response motifs; these enriched for genes involved in plasma cell differentiation. Our results support a model of "kinetic control" in which signaling-induced dynamics of IRF4 in activated B cells control their cell-fate outcomes. Regrettably three of the FASTQ raw sequence files in our study were corrupted during storage. FASTQ data from our experimental and control groups are available for download via GEO SRA; however, two groups are missing select raw sequence files. These include one PU.1 Day 3 group file (Sample GSM1133499) and two of four input files used to generate a concatenated “super” input file (Sample GSM1133490); the raw data provided for input consists of the two input files recovered. Importantly, FASTA sequences for both of these datasets are available as supplementary data through GEO, and we can make available upon request (rsciamma@uchicago.edu) all files in our study in the ELAND-extended alignment format. Please note that GEO no longer supports this format.
2013-05-04 | GSE46608 | 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:Temporal analysis of B cell activation in vitro using CD40L and IL-2/4/5 cytokines in wild type Irf4+/+ B cells or in mutant Irf4-/- B cells harboring a tet-inducible allele of Irf4. IRF4 expression was restored, or not, in the Irf4-/- background by culturing in the presence of low or high concentrations of doxycycline. The results provide insight in the role of IRF4 expression levels in coordinating different programs of B cell differentiation. Resting mature peripheral primary B cells were enriched from the spleens of Irf4+/+ or Irf4-inducible mice on the Irf4-/- background. We sought to compare gene expression profiles of wild type and Irf4 mutant B cells in response to mitogens that promote the differentiation of the B cells into plasma cells and cells that have undergone class switch recombination. Day 0 samples represent RNA analysis of unstimulated cells, whereas Day 1 and Day 3 samples represent analysis of stimulated cells in culture. For stimulation, cells were cultured with insect cell purified CD40L and IL-2/4/5 cytokines for the indicated days. In the case of doxycycline-mediated rescue of IRF4 expression, doxycycline was added at predefined low and high concentrations that yield low or high numbers of plasma cells, respectively (see Molecular Systems Biology 7:495). Each replicate represents analysis of B cells from an individual mouse. Of the three replicates in each group, two were performed in parallel and one was performed at a different time. All cells were lysed using Trizol and total RNA was purified according to manufacturer's suggestions. The high quality of the RNA was confirmed using Agilent Bioanalyzer 2100 system. 250ng of RNA was then processed into biotinylated cRNA according to standard procedures and used to hybridize to Affymetrix 430 2.0 arrays. Signal intensities were normalized using the D-Chip algorithm (PM-only model) and the output was used to quantify differential gene expression between groups.
2013-05-04 | E-GEOD-46606 | biostudies-arrayexpress
Project description:Disease-causing mutations in genes encoding transcription factors (TF) are frequent in hematopoietic malignancies and might affect TF-interactions with respective DNA-binding motifs. Here, we report the characterization of a recurrent somatic mutation c.295T>C in the IRF4 gene in classic Hodgkin lymphoma (cHL) leading to a C99R exchange. IRF4-C99R is located in the center of the IRF4 alpha3-recognition helix contacting the DNA 5´-GAAA-3´ IRF consensus sequence. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs), in particular AP-1-IRF-CEs (AICEs). In line, IRF4-C99R profoundly impairs IRF4-dependent plasma cell induction, and specifically up-regulates degenerate-AICE-dependent distinct cHL disease-characteristic genes. These data document an unprecedented mutation-induced shift of TF binding specificity and its impact for lymphoma pathogenesis and TF modulation.
2023-07-19 | GSE211913 | GEO
Project description:Disease-causing mutations in genes encoding transcription factors (TF) are frequent in hematopoietic malignancies and might affect TF-interactions with respective DNA-binding motifs. Here, we report the characterization of a recurrent somatic mutation c.295T>C in the IRF4 gene in classic Hodgkin lymphoma (cHL) leading to a C99R exchange. IRF4-C99R is located in the center of the IRF4 alpha3-recognition helix contacting the DNA 5´-GAAA-3´ IRF consensus sequence. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs), in particular AP-1-IRF-CEs (AICEs). In line, IRF4-C99R profoundly impairs IRF4-dependent plasma cell induction, and specifically up-regulates degenerate-AICE-dependent distinct cHL disease-characteristic genes. These data document an unprecedented mutation-induced shift of TF binding specificity and its impact for lymphoma pathogenesis and TF modulation.
2023-07-19 | GSE211444 | GEO
Project description:Disease-causing mutations in genes encoding transcription factors (TF) are frequent in hematopoietic malignancies and might affect TF-interactions with respective DNA-binding motifs. Here, we report the characterization of a recurrent somatic mutation c.295T>C in the IRF4 gene in classic Hodgkin lymphoma (cHL) leading to a C99R exchange. IRF4-C99R is located in the center of the IRF4 alpha3-recognition helix contacting the DNA 5´-GAAA-3´ IRF consensus sequence. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs), in particular AP-1-IRF-CEs (AICEs). In line, IRF4-C99R profoundly impairs IRF4-dependent plasma cell induction, and specifically up-regulates degenerate-AICE-dependent distinct cHL disease-characteristic genes. These data document an unprecedented mutation-induced shift of TF binding specificity and its impact for lymphoma pathogenesis and TF modulation.
2023-07-19 | GSE211443 | GEO
Project description:Disease-causing mutations in genes encoding transcription factors (TF) are frequent in hematopoietic malignancies and might affect TF-interactions with respective DNA-binding motifs. Here, we report the characterization of a recurrent somatic mutation c.295T>C in the IRF4 gene in classic Hodgkin lymphoma (cHL) leading to a C99R exchange. IRF4-C99R is located in the center of the IRF4 alpha3-recognition helix contacting the DNA 5´-GAAA-3´ IRF consensus sequence. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs), in particular AP-1-IRF-CEs (AICEs). In line, IRF4-C99R profoundly impairs IRF4-dependent plasma cell induction, and specifically up-regulates degenerate-AICE-dependent distinct cHL disease-characteristic genes. These data document an unprecedented mutation-induced shift of TF binding specificity and its impact for lymphoma pathogenesis and TF modulation.
2023-07-19 | GSE211441 | 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.
2016-01-18 | GSE70981 | GEO