The IL-7 Receptor alpha Promoter Is Activated at Distinct Stages during B Cell Development by the Ets Transcription Factors PU.1 and GABP.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3157-3157
Author(s):  
Rodney P. DeKoter ◽  
Brock L. Schweitzer ◽  
Darrel Jones ◽  
David A. Hildeman ◽  
Kelly J. Huang
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Binding Site ◽  
Progenitor Cells ◽  
Promoter Activity ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development ◽  
Lymphocyte Development

Abstract The cytokine interleukin-7 (IL-7) is required for B and T lymphocyte development, and for the survival and maintenance of both naive and memory T lymphocytes. The receptor for IL-7 (IL-7R) is heterodimeric, consisting of a common gamma chain (γc) and an alpha subunit (IL-7Rα). The γc is expressed in most hematopoietic cell types, but the IL-7Rα gene is regulated in a cell type and developmental stage-specific manner. We have previously shown that the Ets-family transcription factor PU.1 is required to activate transcription of the IL-7Rα gene during fetal lymphocyte development. However, several questions remain unanswered. First, the IL-7Rα promoter is poorly characterized. Second, the IL-7Rα is expressed at high levels in the T cell lineage where PU.1 is not expressed. Third, the transcription factor early B cell factor (EBF) can activate IL-7Rα transcription in developing B cells in the absence of PU.1. To address these questions, we have characterized the IL-7Rα promoter region in detail. First, we determined that the major transcription start sites in the IL-7Rα gene are downstream of an Ets/PU.1 binding site. We found that the intact Ets site is required for IL-7Rα promoter activity, as well as to mediate enhancer action from a distance. IL-7Rα promoter activity depends on the proper orientation of the Ets site relative to functional initiator sequences. We found, using gel shift analysis, that both PU.1 and the Ets transcription factor GA binding protein (GABP) are expressed in developing B cells, and can interact with the Ets binding site in the IL-7Rα promoter. However, the function of PU.1 is distinct from GABP during B cell development. Retroviral transduction of PU.1 mutant progenitor cells with a PU.1 retrovirus robustly rescues IL-7Rα transcription and IL-7-dependent B cell development. In contrast, transduction with GABPα and GABPβ1 subunits fails to activate IL-7Rα transcription in PU.1 mutant progenitor cells. We conclude that activation of the IL-7Rα gene requires PU.1 during the earliest stages of lymphocyte development, but is alternatively utilized by PU.1 and GABP after commitment to the B cell lineage.

scholarly journals Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5857-5867 ◽  
Author(s):  
Teresita L. Arenzana ◽  
Matthew R. Smith-Raska ◽  
Boris Reizis
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development ◽  
Stem Cell Maintenance ◽  
And Function ◽  
Cell Maintenance

Abstract The development, homeostasis, and function of B lymphocytes involve multiple rounds of B-cell receptor (BCR)–controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of hematopoietic stem cell maintenance, in B-cell development and homeostasis. Panhematopoietic or B cell–specific deletion of Zfx in the bone marrow blocked B-cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused accelerated B-cell turnover, depletion of mature recirculating B cells, and delayed T-dependent antibody responses. In addition, the numbers and function of B-1 cell lineage were reduced. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival in vitro. This was accompanied by aberrantly enhanced and prolonged integrated stress response and by delayed induction of cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to cell expansion and maintenance during B-cell development and peripheral homeostasis. These results identify a novel transcriptional regulator of the B-cell lineage and highlight the common genetic control of stem cell maintenance and lymphocyte homeostasis.

scholarly journals Single-cell analysis of developing B cells reveals dynamic gene expression networks that govern B cell development and transformation

2020 ◽  
Author(s):  
Robin D. Lee ◽  
Sarah A. Munro ◽  
Todd P. Knutson ◽  
Rebecca S. LaRue ◽  
Lynn M. Heltemes-Harris ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Rna Binding ◽  
Single Cell Analysis ◽  
Cell Transformation ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development

SummaryIntegration of external signals and B-lymphoid transcription factor activities orchestrate B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells. We used single-cell transcriptomics and proteomics to characterize B cell development. Our analysis revealed unique transcriptional signatures that refine the pre-B cell expansion stages into novel pre-BCR-dependent and pre-BCR-independent proliferative phases. These changes correlate with unexpected dynamic and reciprocal changes in expression of the transcription factor EBF1 and the RNA binding protein YBX3, that are defining features of the pre-BCR-dependent stage. Using pseudotime analysis, we further characterize the expression kinetics of different biological modalities across B cell development, including transcription factors, cytokines, chemokines, and their associated receptors. Our findings reveal the underlying heterogeneity of developing B cells and point to key developmental nodes linked to B cell transformation.

scholarly journals IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF

2005 ◽  
Vol 201 (8) ◽  
pp. 1197-1203 ◽  
Author(s):  
Kazu Kikuchi ◽  
Anne Y. Lai ◽  
Chia-Lin Hsu ◽  
Motonari Kondo
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Target Genes ◽  
Cell Development ◽  
B Cell Development ◽  
Receptor Signaling ◽  
Cell Stage ◽  
Transcription Factor Network ◽  
Stage Transition

Cytokine receptor signals have been suggested to stimulate cell differentiation during hemato/lymphopoiesis. Such action, however, has not been clearly demonstrated. Here, we show that adult B cell development in IL-7−/− and IL-7Rα2/− mice is arrested at the pre–pro-B cell stage due to insufficient expression of the B cell–specific transcription factor EBF and its target genes, which form a transcription factor network in determining B lineage specification. EBF expression is restored in IL-7−/− pre–pro-B cells upon IL-7 stimulation or in IL-7Rα−/− pre–pro-B cells by activation of STAT5, a major signaling molecule downstream of the IL-7R signaling pathway. Furthermore, enforced EBF expression partially rescues B cell development in IL-7Rα−/− mice. Thus, IL-7 receptor signaling is a participant in the formation of the transcription factor network during B lymphopoiesis by up-regulating EBF, allowing stage transition from the pre–pro-B to further maturational stages.

scholarly journals bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.

1996 ◽  
Vol 183 (2) ◽  
pp. 381-391 ◽  
Author(s):  
D A Grillot ◽  
R Merino ◽  
J C Pena ◽  
W C Fanslow ◽  
F D Finkelman ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development ◽  
Immunoglobulin M ◽  
Protective Mechanism ◽  
And Function ◽  
Peripheral B Cells

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

scholarly journals Long noncoding RNAs in B-cell development and activation

Blood ◽  
2016 ◽  
Vol 128 (7) ◽  
pp. e10-e19 ◽  
Author(s):  
Tiago F. Brazão ◽  
Jethro S. Johnson ◽  
Jennifer Müller ◽  
Andreas Heger ◽  
Chris P. Ponting ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Noncoding Rnas ◽  
Cell Development ◽  
B Cell Development ◽  
Long Noncoding Rnas ◽  
Human B Cells

AbstractLong noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia.

scholarly journals The B29 (Immunoglobulin β-Chain) Gene Is a Genetic Target for Early B-Cell Factor

1999 ◽  
Vol 19 (1) ◽  
pp. 392-401 ◽  
Author(s):  
Peter Åkerblad ◽  
Maria Rosberg ◽  
Tomas Leanderson ◽  
Mikael Sigvardsson
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
Chain Gene ◽  
Early B Cell Factor

ABSTRACT Early B-cell factor (EBF) is a transcription factor suggested as essential for early B-lymphocyte development by findings in mice where the coding gene has been inactivated by homologous disruption. This makes the identification of genetic targets for this transcription factor pertinent for the understanding of early B-cell development. The lack of B29 transcripts, coding for the β subunit of the B-cell receptor complex, in pro-B cells from EBF-deficient mice suggested that B29 might be a genetic target for EBF. We here present data suggesting that EBF interacts with three independent sites within the mouse B29 promoter. Furthermore, ectopic expression of EBF in HeLa cells activated a B29promoter-controlled reporter construct 13-fold and induced a low level of expression from the endogenous B29 gene. Finally, mutations in the EBF binding sites diminished B29 promoter activity in pre-B cells while the same mutations did not have as striking an effect on the promoter function in B-cell lines of later differentiation stages. These data suggest that the B29gene is a genetic target for EBF in early B-cell development.

scholarly journals STAT3 positively regulates an early step in B-cell development

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 3005-3011 ◽  
Author(s):  
Wei-Chun Chou ◽  
David E. Levy ◽  
Chien-Kuo Lee
Keyword(s):  
B Cells ◽  
B Cell ◽  
Progenitor Cells ◽  
Cell Development ◽  
B Cell Development ◽  
B Lymphopoiesis ◽  
Cell Compartment ◽  
Immature B Cells ◽  
A Cell ◽  
Deficient Mice

Abstract Transcription factors are critical for instructing the development of B lymphocytes from multipotential progenitor cells in the bone marrow (BM). Here, we show that the absence of STAT3 impaired B-cell development. Mice selectively lacking STAT3 in BM progenitor cells displayed reduced numbers of mature B cells, both in the BM and in the periphery. The reduction in the B-cell compartment included reduced percentages and numbers of pro-B, pre-B, and immature B cells in the absence of STAT3, whereas the number of pre–pro-B cells was increased. We found that pro-B and pre-B–cell populations lacking STAT3 were hyporesponsive to IL-7 because of a decreased number of IL-7–responsive cells rather than decreased expression or signaling of IL-7Rα. Moreover, STAT3-deficient mice displayed enhanced apoptosis in the pro-B population when deprived of survival factors, suggesting that at least 2 mechanisms (impaired differentiation and enhanced apoptosis) are involved in the mutant phenotype. Last, BM transplantation confirmed that impaired B lymphopoiesis in the absence of STAT3 was caused by a cell autonomous defect. In sum, these studies defined a specific role for STAT3 in early B-cell development, probably acting at the pre–pro-B transition by contributing to the survival of IL-7–responsive progenitors.

scholarly journals Single-cell analysis identifies dynamic gene expression networks that govern B cell development and transformation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Robin D. Lee ◽  
Sarah A. Munro ◽  
Todd P. Knutson ◽  
Rebecca S. LaRue ◽  
Lynn M. Heltemes-Harris ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Gene Networks ◽  
Rna Binding ◽  
Single Cell Analysis ◽  
Differentially Expressed Gene ◽  
Cell Development ◽  
B Cell Development

AbstractIntegration of external signals and B-lymphoid transcription factor activities organise B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells. We use single-cell transcriptomics/proteomics to identify differentially expressed gene networks across B cell development and correlate these networks with subtypes of B cell leukemia. Here we show unique transcriptional signatures that refine the pre-B cell expansion stages into pre-BCR-dependent and pre-BCR-independent proliferative phases. These changes correlate with reciprocal changes in expression of the transcription factor EBF1 and the RNA binding protein YBX3, that are defining features of the pre-BCR-dependent stage. Using pseudotime analysis, we further characterize the expression kinetics of different biological modalities across B cell development, including transcription factors, cytokines, chemokines, and their associated receptors. Our findings demonstrate the underlying heterogeneity of developing B cells and characterise developmental nodes linked to B cell transformation.

scholarly journals Regulation of B Lymphocyte Development by Histone H2A Deubiquitinase BAP1

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun Hsiao Lin ◽  
Yue Liang ◽  
HanChen Wang ◽  
Lin Tze Tung ◽  
Michael Förster ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Cycle Progression ◽  
B Lymphocyte ◽  
Cell Development ◽  
B Cell Development ◽  
Lymphocyte Development ◽  
A Cell ◽  
B Lymphocyte Development

BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, via deubiquitination of histone H2AK119ub and other substrates. BAP1 is an important tumor suppressor in human, expressed and functional across many cell-types and tissues, including those of the immune system. B lymphocytes are the mediators of humoral immune response, however the role of BAP1 in B cell development and physiology remains poorly understood. Here we characterize a mouse line with a selective deletion of BAP1 within the B cell lineage (Bap1fl/fl mb1-Cre) and establish a cell intrinsic role of BAP1 in the regulation of B cell development. We demonstrate a depletion of large pre-B cells, transitional B cells, and mature B cells in Bap1fl/fl mb1-Cre mice. We characterize broad transcriptional changes in BAP1-deficient pre-B cells, map BAP1 binding across the genome, and analyze the effects of BAP1-loss on histone H2AK119ub levels and distribution. Overall, our work establishes a cell intrinsic role of BAP1 in B lymphocyte development, and suggests its contribution to the regulation of the transcriptional programs of cell cycle progression, via the deubiquitination of histone H2AK119ub.

Transcription Factor ICSBP/IRF8 Regulates B Cell Development at Multiple Checkpoints.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3314-3314
Author(s):  
Hongsheng Wang ◽  
Chang Hoon Lee ◽  
Chen-Feng Qi ◽  
Nishant Kerrikatte ◽  
Prafullakumar Tailor ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Early Stage ◽  
Consensus Sequence ◽  
Cell Development ◽  
B Cell Development ◽  
Mutant Mice ◽  
Hematopoietic Stem ◽  
B Lineage

Abstract The generation of lymphoid and myeloid lineage cells from hematopoietic stem cells is controlled by multiple transcription factors regulating distinct developmental and functional aspects. Interferon consensus sequence binding protein (ICSBP)/interferon regulatory factor 8 (IRF8) is a transcription factor known to regulate the differentiation of macrophages, granulocytes, and dendritic cells. Our recent findings that IRF8 transcripts and protein are highly expressed in germinal center (GC) B cells suggest that IFR8 may also play a role in normal B cell development. In IRF8 deficient mice, the number of early B lineage cells (pre-pro-B) was reduced by 5-fold, indicating a defect in early B lineage commitment. While the numbers of late pre-B and immature B cells were moderately reduced (~2-fold), recirculating mature B cells were almost undetectable in the bone marrow of mutant mice. This deficiency in early stage B cells is correlated with increased expression of PU.1, a crucial transcription factor for myeloid and lymphoid lineage specification. Interestingly, the number of splenic transitional 1 (T1) cells was slightly increased but the numbers of T2 and follicular (FO) B-2 cells were moderately decreased in mutant mice. This indicates that positive selection of T2 cells into the mature B-2 pool is regulated by IRF8. The marginal zone (MZ) B cell and peritoneal CD11b+ B-1b cell compartments were also slightly expanded in IRF8 knockout mice. Overall, these results provide compelling evidence that IRF8 regulates B cell differentiation and function at multiple stages.

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