Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Wöhner, Miriam; Tagoh, Hiromi; Bilić, Ivan; Jaritz, Markus; Poliakova, Daniela Kostanova; Fischer, Maria; Busslinger, Meinrad

doi:10.1084/jem.20152002

Cited by 92 publications

(122 citation statements)

References 57 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…S1G). B cell-specific deletion of TCF4 did not impair GC B cell numbers or phenotype, and did not affect antibody responses or somatic hypermutation (data not shown), likely due to genetic redundancy with TCF3 (Gloury et al, 2016; Wohner et al, 2016). Thus, the centroblast-specific expression of TCF4 L is not required for centroblast development, but is consistent with a genetically redundant function of TCF4 in these cells.…”

Section: Resultsmentioning

confidence: 89%

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

et al. 2017

View full text Add to dashboard Cite

Summary The cell fate decision between interferon-producing plasmacytoid DC (pDC) and antigen-presenting classical DC (cDC) is controlled by the E protein transcription factor TCF4 (E2-2). We report that TCF4 comprises two transcriptional isoforms, both of which are required for optimal pDC development in vitro. The long Tcf4 isoform is expressed specifically in pDCs, and its deletion in mice impaired pDCs development and led to the expansion of non-canonical CD8+ cDCs. The expression of Tcf4 commenced in progenitors and was further upregulated in pDCs, correlating with stage-specific activity of multiple enhancer elements. A conserved enhancer downstream of Tcf4 was required for its upregulation during pDC differentiation, revealing a positive feedback loop. The expression of Tcf4 and the resulting pDC differentiation were selectively sensitive to the inhibition of enhancer-binding BET protein activity. Thus, lineage-specifying function of E proteins is facilitated by lineage-specific isoform expression and by BET-dependent feedback regulation through distal regulatory elements.

show abstract

Section: Resultsmentioning

confidence: 89%

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Binding sites for Tcf3 (E2A) (53) and Irf4 (54) have also been mapped in primary B cells. We found that ~47% of E2A-binding sites overlap with those of Ets1 (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

“…(51, 53, 54). We used Bedtools to identify the co-occurrence between peaks and common target sites for these transcription factors.…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

et al. 2017

View full text Add to dashboard Cite

BackgroundThe transcription factor Ets1 is highly expressed in B lymphocytes. Loss of Ets1 leads to premature B cell differentiation into antibody-secreting cells (ASCs), secretion of autoantibodies, and development of autoimmune disease. Despite the importance of Ets1 in B cell biology, few Ets1 target genes are known in these cells.ResultsTo obtain a more complete picture of the function of Ets1 in regulating B cell differentiation, we performed Ets1 ChIP-seq in primary mouse B cells to identify >10,000-binding sites, many of which were localized near genes that play important roles in B cell activation and differentiation. Although Ets1 bound to many sites in the genome, it was required for regulation of less than 5% of them as evidenced by gene expression changes in B cells lacking Ets1. The cohort of genes whose expression was altered included numerous genes that have been associated with autoimmune disease susceptibility. We focused our attention on four such Ets1 target genes Ptpn22, Stat4, Egr1, and Prdm1 to assess how they might contribute to Ets1 function in limiting ASC formation. We found that dysregulation of these particular targets cannot explain altered ASC differentiation in the absence of Ets1.ConclusionWe have identified genome-wide binding targets for Ets1 in B cells and determined that a relatively small number of these putative target genes require Ets1 for their normal expression. Interestingly, a cohort of genes associated with autoimmune disease susceptibility is among those that are regulated by Ets1. Identification of the target genes of Ets1 in B cells will help provide a clearer picture of how Ets1 regulates B cell responses and how its loss promotes autoantibody secretion.

show abstract

“…Analysis of an available RNA-seq dataset (Wöhner et al., 2016) enabled investigations of metabolic pathways utilized by CD40/IL-4-activated B cells. A caveat of this approach is that many metabolic processes are regulated allosterically rather than transcriptionally, including glycolysis, so we supplemented our studies with high-throughput metabolic tracing to evaluate consistency in our results.…”

Section: Discussionmentioning

confidence: 99%

Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling

Waters

Ahsan

Wolf³

et al. 2018

iScience

227

216

View full text Add to dashboard Cite

SummaryB lymphocytes provide adaptive immunity by generating antigen-specific antibodies and supporting the activation of T cells. Little is known about how global metabolism supports naive B cell activation to enable an effective immune response. By coupling RNA sequencing (RNA-seq) data with glucose isotopomer tracing, we show that stimulated B cells increase programs for oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and nucleotide biosynthesis, but not glycolysis. Isotopomer tracing uncovered increases in TCA cycle intermediates with almost no contribution from glucose. Instead, glucose mainly supported the biosynthesis of ribonucleotides. Glucose restriction did not affect B cell functions, yet the inhibition of OXPHOS or glutamine restriction markedly impaired B cell growth and differentiation. Increased OXPHOS prompted studies of mitochondrial dynamics, which revealed extensive mitochondria remodeling during activation. Our results show how B cell metabolism adapts with stimulation and reveals unexpected details for carbon utilization and mitochondrial dynamics at the start of a humoral immune response.

show abstract

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Abstract: Busslinger et al. showed that the transcription factors E2A and E2-2 control the expression of genes required for the development of GC B cells and plasma cells.

Cited by 92 publications

References 57 publications

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling

Contact Info

Product

Resources

About