Early B Cell Factor Promotes B Lymphopoiesis with Reduced Interleukin 7 Responsiveness in the Absence of E2A

Seet, Christopher S.; Brumbaugh, Rachel L.; Kee, Barbara L.

doi:10.1084/jem.20032202

Cited by 151 publications

(157 citation statements)

References 45 publications

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“…These cells remain partially blocked in a myeloid state of differentiation (Kita et al, 1992) and despite the expression of transcription factors PAX5, EBF1 and TCF3 (Figure 1b; Supplementary Figures S2b and c), which are essential for and can promote B-cell differentiation (Seet et al, 2004;Kwon et al, 2008), they do not progress to differentiate into B cells and lack B-cell-specific markers such as CD20 and CD21. We therefore propose that the co-expression of transcription factors acting on plastic chromatin and promoting antagonizing gene expression programs is one of the causes for the developmental limbo characteristic for t(8;21) AML cells.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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Correct hematopoietic differentiation requires the tightly regulated execution of lineage-specific and stage-restricted gene expression programs. This process is disturbed in hematological malignancies that typically show incomplete differentiation but often also display a mixed lineage phenotype. Co-expression of lymphoid and myeloid molecules is a well-known feature of acute myeloblastic leukemia (AML) with t(8;21). These cells consistently express the B-cell-specific transcription factor PAX5, and the B-cell-specific cell surface protein CD19. However, the functional consequences of PAX5 expression are unknown. To address this question, we studied the chromatin features of CD19, which is a direct target of PAX5 in cells with and without the t(8;21) chromosomal translocation. We show that CD19 chromatin exists in a poised configuration in myeloid progenitors and that this poised chromatin structure facilitates PAX5-dependent CD19 activation. Our results also show a positive correlation between PAX5 and CD19 expression in t(8;21)-positive AML cells and demonstrate that PAX5 binds to the promoter and enhancer of CD19 gene and remodels chromatin structure at the promoter. This study shows that expression of PAX5 in leukemic cells has functional consequences and points to an important role of a progenitor-specific chromatin configuration in myeloid leukemia.

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Section: Discussionmentioning

confidence: 99%

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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“…E2A and FOXO1, in turn, act in concert to directly activate the expression of EBF1 (30)(31)(32)(33). The induction of EBF1 expression leads to the establishment of a positive feedback circuitry involving EBF1 and FOXO1.…”

Section: Discussionmentioning

confidence: 99%

Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

Månsson

Welinder

Åhsberg

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

100

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Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D + cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1-deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1-and EBF1-deficient LY6D + progenitors are strikingly similar, indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D + CLPs severely affects FOXO1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D + CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1-and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.

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“…Early B-cell Factor (EBF; also known as EBF1/O/E-1/COE1) plays an integral role in this network and has been implicated as a major determinant of the B-cell fate (2,3). In the absence of EBF, B-cell development is arrested at an early progenitor stage (3,4).…”

Section: T He Development Of B Cells From Progenitor Cells In the Bonementioning

confidence: 99%

Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5

Gao

Lukin

Ramírez

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

131

132

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Transcriptionally silent genes are maintained in inaccessible chromatin. Accessibility of these genes requires their modification by chromatin remodeling complexes (CRCs), which are recruited to promoters by sequence-specific DNA-binding proteins. Early B-cell factor (EBF), which is crucial for B-cell lineage specification, reprograms mb-1 (Ig-␣) promoters by increasing chromatin accessibility and initiating the loss of DNA methylation. In turn, this facilitates promoter activation by Pax5. Here, we investigated the roles of ATP-dependent CRCs in these mechanisms. Fusion of EBF and Pax5 with the ligand-binding domain of ER␣ allowed for 4-hydroxytamoxifen-dependent, synergistic activation of mb-1 transcription in plasmacytoma cells. Knockdown of the SWI/SNF ATPases Brg1 and Brm inhibited transcriptional activation by EBF:ER and Pax5:ER. In contrast, knock-down of the Mi-2/NuRD complex subunit Mi-2␤ greatly enhanced chromatin accessibility and mb-1 transcription in response to the activators. The reduction of Mi-2␤ also propagated DNA demethylation in response to EBF:ER and Pax5:ER, resulting in fully unmethylated mb-1 promoters. In EBF-or EBF/Pax5-deficient fetal liver cells, both EBF and Pax5 were required for efficient demethylation of mb-1 promoters. Together, our data suggest that Mi-2/NuRD is important for the maintenance of hypermethylated chromatin in B cells. We conclude that SWI/SNF and Mi-2/NuRD function in opposition to enable or limit the reprogramming of genes by EBF and Pax5 during B-cell development.DNA methylation ͉ mb-1 promoter ͉ Cd19 promoter ͉ chromatin accessibility T he development of B cells from progenitor cells in the bone marrow is controlled by a network of transcriptional regulators (reviewed in 1). Early B-cell Factor (EBF; also known as EBF1/O/E-1/COE1) plays an integral role in this network and has been implicated as a major determinant of the B-cell fate (2, 3). In the absence of EBF, B-cell development is arrested at an early progenitor stage (3, 4). EBF is essential for the rearrangement and expression of Ig (Ig) genes in B cells and is required for expression of the B-cell commitment factor Pax5. EBF and Pax5 synergistically activate transcription of B cell-specific genes including mb-1 (Cd79a), which encodes the Ig-␣ subunit of the pre-B and B-cell receptors (5). We have proposed that EBF functions as a 'pioneer' factor by controlling the epigenetic states of its target genes (6). In response to EBF, the accessibility of mb-1 promoter chromatin is increased, while DNA methylation of the promoter is decreased.Specific biochemical interactions necessary for the pioneer functions of EBF have not been identified. However, transitions between active and inactive states of chromatin can be mediated by the recruitment of chromatin-remodeling complexes (CRCs) by transcription factors (7). CRCs serve as 'molecular motors' that mediate changes in the relative positions of nucleosomes. In this regard, CRCs of the mammalian SWI/SNF (related to yeast switch/sucrose non-Fermenter) subfamily ...

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Early B Cell Factor Promotes B Lymphopoiesis with Reduced Interleukin 7 Responsiveness in the Absence of E2A

Cited by 151 publications

References 45 publications

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5

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