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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (RNA-Seq)

ABSTRACT: Upon antigen recognition B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GC). We uncover a double negative feedback loop between interferon regulatory factors IRF4 and IRF8, which regulates the initial bifurcation of activated B cells as well as the GC response. IRF8 dampens BCR signaling, facilitates antigen specific interaction with helper T cells, and promotes selection of high affinity clones while antagonizing IRF4 driven plasmablast differentiation. Genomic analysis reveals concentration dependent action of IRF4 and IRF8 in regulating distinctive gene expression programs. Stochastic modeling suggests that the double negative feedback is sufficient to initiate bifurcating B cell developmental trajectories. Naïve B cells were isolated from Irf8+/+ (wild type, WT) mice spleen and activated in vitro with 10μg/ml LPS (Sigma). CD138hi IgMhi (IRF4hi*) cells and CD138lo IgMlo (IRF8hi*) cells were sorted by flow cytometry at 72 hours. Total RNA was prepared by using Rneasy Mini kit (Qiagen) and sequenced with Illumina HiSeq2500. Alignment was performed with Taphat2, and transcript abundance quantification using Cuffdiff function from Cufflinks. GC B cells were sorted from CD19cre/+ Irf8+/+ (Ctrl) or CD19cre/+ Irf8flox/flox (Irf8 cKO) mice on dpi 13 post NP-KLH immunization. Total RNA was prepared by using Rneasy Mini kit (Qiagen) and amplified with with Ovation RNA-Seq System v2 (NuGEN). The data were analyzed by Wardrobe. More details are provided in the manuscript.

ORGANISM(S): Mus musculus

SUBMITTER: Harinder Singh

PROVIDER: E-GEOD-70711 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (ChIP-Seq)

Project description:Upon antigen recognition B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GC). We uncover a double negative feedback loop between interferon regulatory factors IRF4 and IRF8, which regulates the initial bifurcation of activated B cells as well as the GC response. IRF8 dampens BCR signaling, facilitates antigen specific interaction with helper T cells, and promotes selection of high affinity clones while antagonizing IRF4 driven plasmablast differentiation. Genomic analysis reveals concentration dependent action of IRF4 and IRF8 in regulating distinctive gene expression programs. Stochastic modeling suggests that the double negative feedback is sufficient to initiate bifurcating B cell developmental trajectories. Naïve B cells were isolated from wild type (WT) mice spleen and activated in vitro with 10μg/ml LPS (Sigma). ChIP was performed by using anti-IRF4, -IRF8 antibodies (Santa Cruz Biotech). For massively parallel sequencing, 10-20 μg of chromatin fragments from indicated samples were immunoprecipitated by using anti-IRF-4 and anti-IRF8 antibodies, and DNA libraries were prepared with Illumina Kit. DNA was sequenced by using the Illumina HiSeq2500. Reads were aligned to the mouse genome (mm9) by using Taphat2 and peak calling were performed by homer 2. GC B cells were sorted from WT mice on dpi 13 post NP-KLH immunization. Cells were flash frozen immediately and process by Active Motif for IRF8 ChIP-Seq. Reads were aligned to mm9 by using BAM and peak calling were performed by using MACS. More details are provided in the manuscript.

2015-08-25 | E-GEOD-70710 | biostudies-arrayexpress

Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (RNA-Seq)

2015-08-25 | GSE70711 | GEO

Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (ChIP-Seq)

2015-08-25 | GSE70710 | GEO

Chip-chip from human diffuse large B cell lymphoma cell lines with IRF8

Project description:IRF8, a transcriptional factor, has the heightened expression in germinal center(GC) B cell and GC-origin B cell lymphoma. To identify IRF8 direct targets in GC B cells, ChIP-chip ananlysis was done in three different GC-origin diffuse large B cell lymphoma cell lines. IRF8-negative cell lines, MMS1, was also used as a negatvie control. IRF8 ChIP in three different cell lines (ODH1, VAL and LY1:high level of IRF8) and in one negative control cell lines (MMS1:negatvie for IRF8). Total four different samples. One sample per a set of two arrays (promoter1 and promoter2).

2011-10-14 | E-GEOD-30357 | biostudies-arrayexpress

Chip-chip from mouse diffuse large B cell lymphoma cell lines with IRF8

Project description:IRF8, a transcriptional factor, has the heightened expression in germinal center(GC) B cell and GC-origin B cell lymphoma. To identify IRF8 direct targets in GC B cells, ChIP-chip ananlysis was done in three different GC-origin diffuse large B cell lymphoma cell lines. IRF8-negative cell lines, MPC11, was also used as a negatvie control. IRF8 ChIP in three different cell lines (NFS201, NFS202 and NFS205:high level of IRF8) and in one negative control cell lines(MPC11:negatvie for IRF8). Total four different samples. One sample per a set of two arrays (promoter1 and promoter2).

2011-10-14 | E-GEOD-30519 | biostudies-arrayexpress

Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-08-25 | E-GEOD-70712 | biostudies-arrayexpress

Genome-wide maps of chromatin state in Germinal Center B cells.

Project description:Protection against deadly pathogens requires the production of high-affinity antibodies by B cells. High-affinity antibody-forming cells are generated in germinal centers (GC) as a result of a developmental program that is commonly altered in B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions including lymphomas. The Histone H3 lysine-27 methyltransferase Enhancer of Zeste homolog 2 (EZH2) is highly expressed in GC B cells and often constitutively activated in GC-derived Non-Hodgkin lymphomas (NHL), but its function in these cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells causes a profound impairment in GC responses, memory B cell formation and humoral immunity. Mechanistically, Ezh2 protected GC B cells against AID mutagenesis, facilitated cell-cycle progression independent of p16INK4a repression and silenced plasma cell determinants Blimp1 and Irf4. Likewise, EZH2 inhibition in GC-derived NHL cells induced tumor suppressor BLIMP1, which impaired tumor growth. In conclusion, in GC B cells Ezh2 sustains AID function and prevents terminal differentiation to allow antibody diversification and affinity maturation. Dysregulation of such mechanisms may facilitate lymphomagenesis and identifies EZH2 as possible therapeutic target in NHL and other GC-derived B cell diseases. In this study, two independent primary samples of splenic GC B cells from C5/BL/6J mice were subjected to H3K27me3 and H3K4me3 ChIP-sequencing. A totale of 6 samples, including input samples, were subjected to ultra-deep sequencing.

2013-12-11 | E-GEOD-50912 | biostudies-arrayexpress

Analysis of TF binding sites and histone modification in IRF8-induced monocyte differentiation

Project description:Chromatins were prepared from myeloid progenitor cell line Tot2 cells transduced with retrovirus for control MSCV or MSCV-IRF8. Chromatin immunoprecipitation (ChIP) was carried out by using anti-IRF8 antibody, anti-PU.1 antibody or anti-histone H3K4me1 antibody. ChIP-Seq peaks were identified using the FindPeaks tool in the HOMER package or SICER with input DNA tags as background distribution. Potential IRF8-direct target genes were identified based on ChIP-Seq and the alteration of expression by IRF8-induction. Examination of 2 transcription factor occupancy and 1 histone modifications in myeloid progenitor cells and monocyte-like cells differetiated by IRF8 expression

2013-01-24 | E-GEOD-38824 | biostudies-arrayexpress

L-Myc expression by dendritic cells is required for optimal T-cell priming

Project description:The transcription factor IRF8 is a critical regulator of plasmacytoid dendritic cell (pDC) and classical dendritic cell (cDC) development in both mouse and man. Yet the downstream molecular targets that regulate DC homeostasis and development are largely unknown. A recent study using gene expression analysis of IRF8-deficient myeloid and lymphoid progenitors identified the Myc paralog Mycl1 as a potential transcriptional target of IRF8. We report here that Mycl1 is a mediator of DC homeostasis at steady state and during inflammation, and its expression is regulated by IRF8 in multiple DC lineages. We have further validated these observations with ChIP-Seq of IRF8 binding to the Mycl1 locus. Notably, IRF8 binding to Mycl1 locus is independent of an interaction with the AP1 factor, BATF3. Additionally, our genome-wide survey of IRF8 binding identified both EICE and AICE motifs. Examination of IRF8 binding in dendritic cells

2013-12-14 | E-GEOD-53311 | biostudies-arrayexpress

Development of plasma cell-prone germinal center B cells

Project description:Higher- or lower-affinity GC B cells are directed to plasma cell or recycling GC cell fates; however, how commitment to the plasma cell fate takes place is unclear. By using the level of Bcl6 as a marker, we found that a population of light zone (LZ) GC cells, Bcl6loCD69hi with IRF4 and higher-affinity BCRs or Bcl6hiCD69hi with lower- affinity BCRs, favored the plasma cell or recycling GC cell fate, respectively. Mechanistically, CD40 acted as a dose-dependent regulator for Bcl6loCD69hi cell formation. Furthermore, we found that ICAM1 and SLAM levels on Bcl6loCD69hi cells were higher than on Bcl6hiCD69hi cells, thereby affording more stable TFH-GC B cell contacts, while attenuating this contact down-regulated IRF4. These data support the model that commitment to the plasma cell begins in the GC, and suggest that stability and possibly duration of TFH-GC B cell contacts are key for formation of plasma cell-prone precursor GC cells.

2018-03-29 | GSE109732 | GEO

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