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A global network of transcription factors, involving E2A, EBF1 and FOXO1, that orchestrates the B cell fate

ABSTRACT: It is now established that the transcription factors E2A, EBF1 and Foxo 1 play critical roles in B cell development. Here we show that E2A and EBF1 bound regulatory elements present in the Foxo1 locus. E2A and EBF1 as well as E2A and Foxo1, in turn, were wired together by a vast spectrum of cis-regulatory codes. These associations were dynamic during developmental progression. Occupancy by the E2A isoform, E47, directly elevated the abundance as well as the pattern of histone H3K4 monomethylation across putative enhancer regions. Finally, the pro-B cell epigenome was divided into clusters of loci that show E2A, EBF and Foxo1 occupancy. From this analysis a global network consisting of transcriptional regulators, signaling and survival factors, was constructed that we propose orchestrates the B cell fate.

ORGANISM(S): Mus musculus

PROVIDER: GSE21978 | GEO | 2010/06/13

SECONDARY ACCESSION(S): PRJNA127185

REPOSITORIES: GEO

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A global network of transcription factors, involving E2A, EBF1 and FOXO1, that orchestrates the B cell fate

Project description:It is now established that the transcription factors E2A, EBF1 and FoxoM-BM- 1 play critical roles in B cell development. Here we show that E2A and EBF1 bound regulatory elements present in the Foxo1 locus. E2A and EBF1 as well as E2A and Foxo1, in turn, were wired together by a vast spectrum of cis-regulatory codes. These associations were dynamic during developmental progression. Occupancy by the E2A isoform, E47, directly elevated the abundance as well as the pattern of histone H3K4 monomethylation across putative enhancer regions. Finally, the pro-B cell epigenome was divided into clusters of loci that show E2A, EBF and Foxo1 occupancy. From this analysis a global network consisting of transcriptional regulators, signaling and survival factors, was constructed that we propose orchestrates the B cell fate. ChIP-Seq and gene expression profiling was performed in a variety of genetically modified primary B cell populations and cell lines approximating developmental stages of B cell development.

2010-06-12 | E-GEOD-21978 | biostudies-arrayexpress

Microarray analysis of E2a-/- and E2a/-Lef1F/F leukemia lines after retroviral Cre expression

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Project description:The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the proto-oncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells following restoration of E2A expression, we identify a number of E2A-regulated genes that interfere with oncogenic signaling pathways including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity. The E2A-deficient Sézary cell line Seax was transiently transfected with the E2A-expression constructs E47myc (a myc-tagged E47 construct) or E47-forced dimer (a construct coding for two covalently linked E47 molecules), respectively. Every experiment was performed as two replicates accompanied by control transfections with a Mock plasmid.

2011-07-07 | E-GEOD-21730 | biostudies-arrayexpress

Microarray analysis to identify genes that are differentially expressed in resting and in LPS-activated splenic B cells of Ebf1+/fl-RERTCre and Ebf1fl/fl-RERTCre mice

2012-04-03 | GSE36061 | GEO

Microarray analysis to identify genes that are differentially expressed in resting and in LPS-activated splenic B cells of Ebf1+/fl-RERTCre and Ebf1fl/fl-RERTCre mice

Project description:Using resting and LPS-stimulated B cells from mice carrying two Ebf1 alleles flanked with loxP sites and an inducible Cre recombinase, target genes of Ebf 1 and the effect of Ebf1 deletion on the cells was analyzed. Target genes of Ebf 1 and the effect of Ebf1 deletion on the cells was analyzed. Ebf1 fl/fl mice and heterozygote control animals carrying an ER-Cre fusion protein were treated with Tamoxifen-Citrate and were sacrificed for analysis. Resting B cells were sorted and were either left untreated or were stimulated with LPS, followed by RNA extraction for expression analysis. See related Series GSE35915.

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RNA-sequencing of E2a-deficient or E2a and Lef1-deficient leukemia cell lines

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Opposing roles of E2A and Id3 that orchestrate and enforce the naive T cell fate

Project description:It is established that E2A and its antagonist, Id3, modulate developmental progression at the pre-TCR and TCR checkpoints. Here we show at a global scale how E2A promotes commitment to the T cell lineage and how pre-TCR mediated signalling affects E2A genome-wide occupancy. We find aberrant development of CD4 memory-like and TFH-like cells, T-B cell conjugates and, remarkably, B cell follicles in Id3-/-thymi. We also find that Id3-/-CD4 splenocytes exhibit increased numbers of TFH-like cells. We propose a model in which Id3 modulates the naive versus effector/memory cell fate. Collectively, these data show how E2A acts globally to orchestrate T-lineage development and that Id3 antagonizes E2A activity beyond the pre-TCR checkpoint to enforce the naive T cell fate.

2011-07-31 | GSE30518 | GEO

Opposing roles of E2A and Id3 that orchestrate and enforce the naive T cell fate

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Expression profiling of early lymphoid progenitors deficient for Ebf1 and Foxo1

Project description:Foxo1 and Ebf1 deficiency leads to a similar disruption of normal B-cell development at the level of the common lymphoid progenitor (CLP). Both mouse strains display the existance of LY6D+ CLPs but a marked/complete lack of proB cells. To investigate similarities of the developmental defects observed we generated gene expression profiles from both genotypes (with corresponding WT controls). This illustrated a shared gene expression signature in Ebf1/Foxo1 deficient CLPs. Gene expression profiling was done using highly purified (FACS sorted) progenitor cells. Cells were purified from bone marrow of wild-type, Foxo1 deficient and Ebf1 deficient mice. Ebf1 deficient bone marrow was aquired by transplantation of Ebf1 deficient progenitors into irradiated hosts. Populations analysed were CLP LY6D-, CLP LY6D+ and proB cells.

2012-11-01 | E-GEOD-41931 | biostudies-arrayexpress

The role of the bHLH factor E47 in modulating hepatic glucocorticoid receptor action (metabolism) [ChIP-seq]

Project description:We performed ChIP-Sequencing for E2A and GR in mouse livers and demonstrate that E47 co-occupies metabolic promoters and enhancers together with GR. Together with the corresponding RNA-Seq data, our results illustrate how GR and E47 synergize during the transcriptional activation of hepatic metabolism.

2018-11-30 | GSE111526 | GEO

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