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Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferative expansion and survival of B cells [H3K4me2 and H3K4me3]

ABSTRACT: Transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into differentiation stage-specific functions of Ebf1, we conditionally inactivated Ebf1. We found that Ebf1 is required for proliferation, survival and signaling of pro-B cells and peripheral B cell subsets. The proliferation defect of Ebf1-deficient pro-B cells, including the impaired expression of IL-7Ra and several cell cycle regulators, is overcome by transformation with v-Abl. The survival defect of transformed Ebf1fl/fl pro-B cells can be rescued by the forced expression of the Ebf1 targets c-Myb or Bcl-xL. In mature B cells, Ebf1 deficiency interferes with the BAFF-R and BCR-dependent Akt signaling pathways, as well as with germinal center formation and class switch recombination. Genome-wide analyses of Ebf1 binding and Ebf1-mediated gene expression in mature B cells and comparison with reported data sets in pro-B cells provide insight into the basis for lineage- and stage-specific functions of Ebf1.

ORGANISM(S): Mus musculus

PROVIDER: GSE35914 | GEO | 2012/04/03

SECONDARY ACCESSION(S): PRJNA155699

REPOSITORIES: GEO

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Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferative expansion and survival of B cells [H3K4me2 and H3K4me3]

Project description:Transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into differentiation stage-specific functions of Ebf1, we conditionally inactivated Ebf1. We found that Ebf1 is required for proliferation, survival and signaling of pro-B cells and peripheral B cell subsets. The proliferation defect of Ebf1-deficient pro-B cells, including the impaired expression of IL-7Ra and several cell cycle regulators, is overcome by transformation with v-Abl. The survival defect of transformed Ebf1fl/fl pro-B cells can be rescued by the forced expression of the Ebf1 targets c-Myb or Bcl-xL. In mature B cells, Ebf1 deficiency interferes with the BAFF-R and BCR-dependent Akt signaling pathways, as well as with germinal center formation and class switch recombination. Genome-wide analyses of Ebf1 binding and Ebf1-mediated gene expression in mature B cells and comparison with reported data sets in pro-B cells provide insight into the basis for lineage- and stage-specific functions of Ebf1. Localistaion of histone modification (H3K4me2 and H3K4me3) in splenic B cells in mice by ChIP-seq

2012-04-02 | E-GEOD-35914 | biostudies-arrayexpress

Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferative expansion and survival of B cells [EBF1]

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Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferative expansion and survival of B cells [EBF1]

2012-04-03 | GSE35910 | GEO

IGH analysis in pro-B cells with H3K4me3, H3K4me2 and H3K9ac

Project description:STAT5 and IL-7 signaling are thought to control B-lymphopoiesis by regulating key transcription factor genes and activating VH gene segments at the Igh locus. Using conditional mutagenesis, we demonstrate that transgenic Bcl2 expression rescued the development of Stat5-deleted pro-B cells by compensating for the loss of Mcl-1. Ebf1 and Pax5 expression as well as VH recombination were normal in Bcl2-rescued pro-B cells lacking STAT5 or IL-7Ra. In agreement with this finding, STAT5-expressing pro-B cells contained little or no active chromatin at most VH genes. In contrast, Igk rearrangements were increased in STAT5- or IL-7Ra-deficient pro-B cells, consistent with direct binding of STAT5 to the intronic iEk enhancer in wild-type pro-B cells. Hence, STAT5 and IL-7 signaling control cell survival and suppress premature Igk recombination in early B-lymphopoiesis. comparison of wt vs Rag2-/- pro-B cells

2010-07-28 | E-GEOD-18278 | biostudies-arrayexpress

IGH analysis in pro-B cells with H3K4me3, H3K4me2 and H3K9ac

2010-07-28 | GSE18278 | GEO

Essential role of EBF1 in B cell immunity by controlling the generation and function of distinct mature B cell types

Project description:The transcription factor EBF1 is essential for lineage specification in early B cell development. Here we demonstrate by conditional mutagenesis that EBF1 was required for B cell commitment, pro-B cell development and subsequent transition to pre-B cells. Later in B cell development, EBF1 was essential for the generation and maintenance of distinct mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular and germinal center B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient follicular B cells. Immune responses were severely reduced upon Ebf1 inactivation, as germinal centers were formed but not maintained. ChIP- and RNA-sequencing of follicular B cells identified EBF1-activated genes that code for receptors, signal transducers and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity. 29 samples (4 ChIP-seq,16 input, 9 RNA-seq), All ChIP-seq in 2 biological replicates, but EBF1 ChIP-seq Pro-B in 2 technical replicates; All RNA-seq in 2 biological replicates but RNA-seq mature B_FO B_Cd23-Cre Ebf1(fl/–). WT and experimental samples are provided.

2012-03-20 | E-GEOD-35857 | biostudies-arrayexpress

A comprehensive Proteomic Investigation of Ebf1 Heterozygosity in pro-B lymphocytes utilizing Data Independent Acquisition

Project description:Early B cell factor 1 (EBF1) is one of the key transcription factors required for orchestrating B-cell lineage development. Although studies have shown that Ebf1 haploinsufficiency is involved in the development of leukemia, no study has been conducted that characterizes the global effect of Ebf1 heterozygosity on the proteome of pro-B lymphocytes. Here, we employ both DIA (Data Independent Acquisition) and shotgun DDA (Data Dependent Acquisition) workflows for profiling proteins that are differently expressed between Ebf1+/+ and Ebf1+/- cells. Both DDA and DIA were able to reveal the downregulation of the EBF1 transcription factor in Ebf1+/- pro-B lymphocytes. Further examination of differentially expressed proteins by DIA revealed that, similar to EBF1, the expression of other B-cell lineage regulators, such as TCF3 and Pax5, is also down-regulated in Ebf1 heterozygous cells. Functional DIA analysis of differentially expressed proteins showed that EBF1 heterozygosity resulted in the deregulation of at least 8 transcription factors involved in lymphopoiesis, and to the deregulation of key proteins playing crucial roles in survival, development and differentiation of pro-B lymphocytes.

2017-12-20 | PXD008396 | Pride

Genome-wide mapping of EBF1 binding sites in murine pre B-cells

Project description:Early B cell factor-1 (Ebf1), a transcription factor expressed in B cells, adipocytes and neuronal cells, has been identified as a determinant in the specification of the B cell lineage in which Ebf1 acts in a regulatory network with the transcription factors E2A and Pax5. To gain insight into the molecular basis of Ebf1 function in early stage B cells, we compared the data set of a genome-wide ChIP sequencing analysis with gain- and loss-of-function transcriptome analyses. Identification of genetic loci enriched by chromatin-immunoprecipitation using antibodies against EBF1.

2010-05-06 | E-GEOD-19971 | biostudies-arrayexpress

The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program

Project description:Mature lymphoid cells express the transcriptional repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells (‘myeloid genes’). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2hi CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.

2014-10-26 | GSE61409 | GEO

Gene expression analysis after reconstitution of Ebf1-deficient pre-pro-B cells with Ebf1

Project description:Ebf1 deficient pre-pro B-cells (Fraction A) can be cultured in the presence of stromal feeders and cytokines. The retroviral transduction of these cells with Ebf1 was used as gain-of-function experiment for the analysis of direct and functional target genes of Ebf1. Ebf1 deficient pre-pro B-cells were retrovirally transduced with an Ebf1-expressing or control retrovirus. 24h after transduction the infected cells were isolated and their gene expression profile was compared.

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