Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription

Maier, Holly; Ostraat, Rachel; Gao, Hua; Fields, Scott; Shinton, Susan A.; Medina, Kay L.; Ikawa, Tomokatsu; Murre, Cornelis; Singh, Harinder; Hardy, Richard R.; Hagman, James

doi:10.1038/ni1119

Cited by 167 publications

(180 citation statements)

References 43 publications

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“…Previously, we concluded that EBF increases the accessibility of mb-1 promoter DNA (22). In turn, this facilitates DNA binding and activation of the promoter by Pax5.…”

Section: -Oht-dependent Ebf and Pax5mentioning

confidence: 79%

“…Unlike M.10 cells, M.2 cells are refractory to activation by Pax5 because their mb-1 promoters are uniformly hypermethylated in relatively inaccessible chromatin (21,22). Following incubation with 4-OHT (Fig.…”

Section: -Oht-dependent Ebf and Pax5mentioning

confidence: 99%

“…Our previous studies demonstrated that mb-1 promoter activation is blocked, in part, by DNA methylation because 5-methylcytosine (5-meC) interferes with Pax5's recruitment of Ets transcription factors to bind mb-1 promoters in M.2 cells (21,22). Our observation that mb-1 transcripts are increased efficiently by EBF:ER, Pax5:ER and the knock-down of Mi-2␤ suggested that these conditions result in demethylation of mb-1 promoters.…”

Section: Demethylation Of Mb-1 Promoters In Response To Ebf and Pax5 Ismentioning

confidence: 99%

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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.

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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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“…Previously, we concluded that EBF increases the accessibility of mb-1 promoter DNA (22). In turn, this facilitates DNA binding and activation of the promoter by Pax5.…”

Section: -Oht-dependent Ebf and Pax5mentioning

confidence: 79%

Section: -Oht-dependent Ebf and Pax5mentioning

confidence: 99%

Section: Demethylation Of Mb-1 Promoters In Response To Ebf and Pax5 Ismentioning

confidence: 99%

See 1 more Smart Citation

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.

Self Cite

131

132

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“…3). Alternatively, CLPs can differentiate to T-cells through Notch1 activation, which is negatively regulated by PAX5 [166][167][168] . Recent studies have shown the role of FOXP1 in the transition of pro-B cells to pre-B cells, a step which is also controlled by IRF4/MUM1 and IRF8 169,170 .…”

Section: Do Lymphoid Malignancies Arise From Mutations That Deregulatmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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“…In particular, the binding of EBF1 to chromatin has been shown to correlate with dimethylation of Lys4 of histone H3 (Treiber et al 2010b). In addition, the function of EBF1 has been associated with SWI/SNF-dependent remodeling of chromatin and DNA demethylation of some promoters (Maier et al 2004;Gao et al 2009;Boller et al 2016). However, no physical interaction between EBF1 and SWI/SNF proteins has yet been demonstrated.…”

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confidence: 99%

Interaction of CCR4–NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis

et al. 2016

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Transcription factor EBF1 (early B-cell factor 1) regulates early B-cell differentiation by poising or activating lineagespecific genes and repressing genes associated with alternative cell fates. To identify proteins that regulate the diverse functions of EBF1, we used SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry of proteins associated with endogenous EBF1 in pro-B cells. This analysis identified most components of the multifunctional CCR4-NOT complex, which regulates transcription and mRNA degradation. CNOT3 interacts with EBF1, and we identified histidine 240 in EBF1 as a critical residue for this interaction. Complementation of Ebf1 −/− progenitors with EBF1H240A revealed a partial block of pro-B-cell differentiation and altered expression of specific EBF1 target genes that show either reduced transcription or increased mRNA stability. Most deregulated EBF1 target genes show normal occupancy by EBF1H240A, but we also detected genes with altered occupancy, suggesting that the CCR4-NOT complex affects multiple activities of EBF1. Mice with conditional Cnot3 inactivation recapitulate the block of early B-cell differentiation, which we found to be associated with an impaired autoregulation of Ebf1 and reduced expression of pre-B-cell receptor components. Thus, the interaction of the CCR4-NOT complex with EBF1 diversifies the function of EBF1 in a context-dependent manner and may coordinate transcriptional and post-transcriptional gene regulation.

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Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription

Cited by 167 publications

References 43 publications

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

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

Somatic stem cells and the origin of cancer

Interaction of CCR4–NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis

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