The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor

Department of Molecular Biology, University of California at San Diego, La Jolla, CA 92093, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2011; 108(42):17402-7. DOI: 10.1073/pnas.1111766108
Source: PubMed


Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A(+/-)HEB(-/-) mice is completely blocked at the LY6D(-) common lymphoid progenitor stage. We show that the transcription signatures of E2A- and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D(-) HEB- and E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB.

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Available from: Cornelis Murre, Dec 24, 2013
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    • "). E2A activity regulates a large number of genes in B cells, often in conjunction with Ebf1 and Pax5 (Lin et al. 2010). One important E2A target is Foxo1 that in turn then acts with E2A and HeLa E-box binding protein (HEB) to support B cell programming (Welinder et al. 2011) (Fig. 2). The role of Foxo1 will be discussed in further detail below. "
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    ABSTRACT: The differentiation of early B cell progenitors is controlled by multiple transcriptional regulators and growth-factor receptors. The triad of DNA-binding proteins, E2A, EBF1, and PAX5 is critical for both the early specification and commitment of B cell progenitors, while a larger number of secondary determinants, such as members of the Ikaros, ETS, Runx, and IRF families have more direct roles in promoting stage-specific pre-B gene-expression program. Importantly, it is now apparent that mutations in many of these transcription factors are associated with the progression to acute lymphoblastic leukemia. In this review, we focus on recent studies that have shed light on the transcriptional hierarchy that controls efficient B cell commitment and differentiation as well as focus on the oncogenic consequences of the loss of many of the same factors.
    Full-text · Article · May 2014 · Current topics in microbiology and immunology
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    • "E2A-null mutant mice fail to generate LMPPs and lack B cells (43). E2A acts synergistically with PU.1 and is required for Ebf1 and FoxO1 expression at the CLP stage (45, 46). Genome-wide mapping experiments in B cell progenitors (Ebf1−/− and Rag2−/−) showed that E2A binds both TSSs and putative enhancers (24) and is required to induce H3K4me1 deposition at enhancer elements in concert with PU.1 (30). "
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    ABSTRACT: All mature blood cells derive from hematopoietic stem cells through gradual restriction of their cell fate potential and acquisition of specialized functions. Lineage specification and cell commitment require the establishment of specific transcriptional programs involving the activation of lineage-specific genes and the repression of lineage-inappropriate genes. This process requires the concerted action of transcription factors (TFs) and epigenetic modifying enzymes. Within the hematopoietic system, B lymphopoiesis is one of the most-studied differentiation programs. Loss of function studies allowed the identification of many TFs and epigenetic modifiers required for B cell development. The usage of systematic analytical techniques such as transcriptome determination, genome-wide mapping of TF binding and epigenetic modifications, and mass spectrometry analyses, allowed to gain a systemic description of the intricate networks that guide B cell development. However, the precise mechanisms governing the interaction between TFs and chromatin are still unclear. Generally, chromatin structure can be remodeled by some TFs but in turn can also regulate (i.e., prevent or promote) the binding of other TFs. This conundrum leads to the crucial questions of who is on first, when, and how. We review here the current knowledge about TF networks and epigenetic regulation during hematopoiesis, with an emphasis on B cell development, and discuss in particular the current models about the interplay between chromatin and TFs.
    Full-text · Article · Apr 2014 · Frontiers in Immunology
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    • "These cells were identified by a lack of lineage specific markers (lin-) and expression of sca-1 and c-kit on their surface. The lin-sca+kit+ (LSK) population contained the earliest bone marrow progenitors: hematopoietic stem cells (HSCs) were identified by gating on the CD105+ and CD150+ population whereas multipotent progenitors (MPPs) were identified by gating on the CD105+ CD150- cell subset, as described in [13]. The LK compartment (lin-sca-kit+) is known to contain myeloid and erythroid progenitors (Additional file 2: Figure S2) [14]. "
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    ABSTRACT: Background ZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to specific DNA binding sites in the Moloney murine leukemia virus (Mo-MuLV) promoter and is required for efficient viral mRNA transcription (J. Virol. 84:7473-7483, 2010). Methods To determine whether this cellular factor influences Mo-MuLV replication and viral disease pathogenesis in vivo, we generated a ZASC1 knockout mouse model and completed both early infection and long term disease pathogenesis studies. Results Mice lacking ZASC1 were born at the expected Mendelian ratio and showed no obvious physical or behavioral defects. Analysis of bone marrow samples revealed a specific increase in a common myeloid progenitor cell population in ZASC1-deficient mice, a result that is of considerable interest because osteoclasts derived from the myeloid lineage are among the first bone marrow cells infected by Mo-MuLV (J. Virol. 73: 1617-1623, 1999). Indeed, Mo-MuLV infection of neonatal mice revealed that ZASC1 is required for efficient early virus replication in the bone marrow, but not in the thymus or spleen. However, the absence of ZASC1 did not influence the timing of subsequent tumor progression or the types of tumors resulting from virus infection. Conclusions These studies have revealed that ZASC1 is important for myeloid cell differentiation in the bone marrow compartment and that this cellular factor is required for efficient Mo-MuLV replication in this tissue at an early time point post-infection.
    Full-text · Article · Apr 2013 · Virology Journal
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