The mechanism of repression of the myeloid-specific c-fms gene by Pax5 during B lineage restriction
08 Mar 2006-The EMBO Journal (European Molecular Biology Organization)-Vol. 25, Iss: 5, pp 1070-1080
TL;DR: The results support a model by which Pax5 does not lead to major alterations in chromatin modification, but inhibits transcription by interfering with the action of myeloid transcription factors.
Abstract: The transcription factor Pax5 (BSAP) is required for the expression of a B-cell-specific genetic program and for B-cell differentiation, and also to suppress genes of alternative lineages. The molecular mechanism by which repression of myeloid genes occurs during early B-lineage restriction is unknown and in this study we addressed this question. One of the genes repressed by Pax5 in B cells is the colony-stimulating factor receptor 1 gene (csf1r or c-fms). We examined the changes in chromatin caused by Pax5 activity, and we show that Pax5 is directly recruited to c-fms resulting in the rapid loss of RNA polymerase II binding, followed by loss of transcription factor binding and DNaseI hypersensitivity at all cis-regulatory elements. We also show that Pax5 targets the basal transcription machinery of c-fms by interacting with a binding site within the major transcription start sites. Our results support a model by which Pax5 does not lead to major alterations in chromatin modification, but inhibits transcription by interfering with the action of myeloid transcription factors.
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TL;DR: Conditional Pax5 inactivation in early and late B lymphocytes revealed an essential role in controlling the identity and function of B cells throughout B lymphopoiesis, and was implicated in human B cell malignancies.
Abstract: The transcription factor Pax5 is essential for commitment of lymphoid progenitors to the B lymphocyte lineage. Pax5 fulfils a dual role by repressing B lineage 'inappropriate' genes and simultaneously activating B lineage-specific genes. This transcriptional reprogramming restricts the broad signaling capacity of uncommitted progenitors to the B cell pathway, regulates cell adhesion and migration, induces V(H)-DJ(H) recombination, facilitates (pre-)B cell receptor signaling and promotes development to the mature B cell stage. Conditional Pax5 inactivation in early and late B lymphocytes revealed an essential role for Pax5 in controlling the identity and function of B cells throughout B lymphopoiesis. PAX5 has also been implicated in human B cell malignancies, as it is deregulated by chromosomal translocations in a subset of acute lymphoblastic leukemias and non-Hodgkin lymphomas.
609 citations
Cites background from "The mechanism of repression of the ..."
...Lastly, the characterization of Csf1r and Flt3 as direct Pax5 target genes indicated that Pax5 is able to mediate gene repression by binding to proximal promoter region...
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TL;DR: This review describes the pathways regulating macrophage survival, proliferation, differentiation, and chemotaxis downstream from the CSF-1R and describes the mechanism of ligand binding to and activation of the receptor.
Abstract: The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). It plays important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia. It also regulates the differentiation of neural progenitor cells and controls functions of oocytes and trophoblastic cells in the female reproductive tract. Owing to this broad tissue expression pattern, it plays a central role in neoplastic, inflammatory, and neurological diseases. In this review we summarize the evolution, structure, and regulation of expression of the CSF-1R gene. We discuss the structures of CSF-1, IL-34, and the CSF-1R and the mechanism of ligand binding to and activation of the receptor. We further describe the pathways regulating macrophage survival, proliferation, differentiation, and chemotaxis downstream from the CSF-1R.
487 citations
Additional excerpts
...1D) (Tagoh et al. 2006; Bonifer and Hume 2008)....
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TL;DR: PU.1 directs the hematopoietic stem cell to the lymphoid-myeloid progenitor (LMP) and interacts with GATA-binding protein 1 to inhibit commitment to the megakaryocyte-erythroid progenitors (GMP) stage, while inhibiting lymphoid development via cross-inhibition of Pax5 and potentially other regulators.
Abstract: PU.1 directs the hematopoietic stem cell to the lymphoid-myeloid progenitor (LMP) and interacts with GATA-binding protein 1 to inhibit commitment to the megakaryocyte-erythroid progenitor. The CCAAT/enhancer-binding protein (C/EBP)alpha then directs the LMP to the granulocyte-monocyte progenitor (GMP) stage, while inhibiting lymphoid development via cross-inhibition of Pax5 and potentially other regulators. Increased PU.1 activity favors monocytic commitment of the GMP. Induction of PU.1 by C/EBPalpha and interaction of PU.1 with c-Jun elevates PU.1 activity. Zippering of C/EBPalpha with c-Jun or c-Fos also contributes to monocyte lineage specification. An additional factor, potentially an Id1-regulated basic helix-loop-helix protein, may be required for the GMP to commit to the granulocyte lineage. Egr-1, Egr-2, Vitamin D Receptor, MafB/c: Fos and PU.1:interferon regulatory factor 8 complexes direct further monocytic maturation, while retinoic acid receptor (RAR) and C/EBPepsilon direct granulopoiesis. Both C/EBPalpha and RARs induce C/EBPepsilon, and PU.1 is also required, albeit at lower levels, for granulocytic maturation. HoxA10 and CAAT displacement protein act as transcriptional repressors to delay expression of terminal differentiation. Gfi-1 and Egr-1,2/Nab2 complexes repress each other to maintain myeloid lineage fidelity. NF-kappaB directly binds and cooperates with C/EBPbeta to induce the inflammatory response in mature myeloid cells and potentially also cooperates with C/EBPalpha to regulate early myelopoiesis.
412 citations
Cites background from "The mechanism of repression of the ..."
...Pax5 also represses the MCSFR promoter through direct interaction (Tagoh et al., 2006)....
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TL;DR: This review focuses on recent studies that have revealed that instead of a simple transcriptional hierarchy, efficient B cell commitment and differentiation requires the combinatorial activity of multiple transcription factors in a complex gene regulatory network.
359 citations
TL;DR: It is shown that the transcription factor EBF restored the generation of CD19+ pro–B cells from Ikaros-deficient hematopoietic progenitors, and is an obligate component of a network that regulates B cell fate commitment and immunoglobulin heavy-chain gene recombination.
Abstract: The transcription factor Ikaros is essential for B cell development. However, its molecular functions in B cell fate specification and commitment have remained elusive. We show here that the transcription factor EBF restored the generation of CD19(+) pro-B cells from Ikaros-deficient hematopoietic progenitors. Notably, these pro-B cells, despite having normal expression of the transcription factors EBF and Pax5, were not committed to the B cell fate. They also failed to recombine variable gene segments at the immunoglobulin heavy-chain locus. Ikaros promoted heavy-chain gene rearrangements by inducing expression of the recombination-activating genes as well as by controlling accessibility of the variable gene segments and compaction of the immunoglobulin heavy-chain locus. Thus, Ikaros is an obligate component of a network that regulates B cell fate commitment and immunoglobulin heavy-chain gene recombination.
252 citations
References
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TL;DR: It is proposed that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
Abstract: Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
9,309 citations
"The mechanism of repression of the ..." refers background in this paper
...…Biology Organization The EMBO Journal VOL 25 | NO 5 | 2006 1073 Repression of gene expression often involves the acquisition of inactive histone marks and the loss of active histone marks such as histone H3 lysine 4 methylation or lysine 9 acetylation, respectively (Jenuwein and Allis, 2001)....
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TL;DR: The developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor, and mice carrying a mutation in the PU.1 locus were generated by gene targeting.
Abstract: The transcription factor PU.1 is a hematopoietic-specific member of the ets family. Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. Mutant embryos produced normal numbers of megakaryocytes and erythroid progenitors, but some showed an impairment of erythroblast maturation. An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor.
1,546 citations
"The mechanism of repression of the ..." refers background in this paper
...PU.1 is an essential factor regulating c-fms expression, and elimination of this factor abolishes c-fms expression and blocks macrophage differentiation (Scott et al, 1994; Simon et al, 1996)....
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TL;DR: A comprehensive picture of events resulting in transcriptional activation of a gene is provided, through evaluating the estrogen receptor-alpha (NR3A1) target pS2 gene promoter in MCF-7 cells, which implies that transcriptionalactivation is a cyclical process that requires both activating and repressive epigenetic processes.
1,473 citations
"The mechanism of repression of the ..." refers background in this paper
...…here, the consequence of this abrogation of activated transcription is a rapid loss of RNA-polymerase II binding, confirming published data demonstrating that the frequency of initiating a new transcription cycle is crucially dependent on the binding of upstream activators (Metivier et al, 2003)....
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TL;DR: It is shown that pro-B cells lacking Pax5 are also incapable of in vitro B-cell differentiation unless Pax5 expression is restored by retroviral transduction, and Pax5 plays an essential role in B-lineage commitment by suppressing alternative lineage choices.
Abstract: The Pax5 gene encoding the B-cell-specific activator protein (BSAP) is expressed within the haematopoietic system exclusively in the B-lymphoid lineage, where it is required in vivo for progression beyond the pro-B-cell stage. However, Pax5 is not essential for in vitro propagation of pro-B cells in the presence of interleukin-7 and stromal cells. Here we show that pro-B cells lacking Pax5 are also incapable of in vitro B-cell differentiation unless Pax5 expression is restored by retroviral transduction. Pax5-/- pro-B cells are not restricted in their lineage fate, as stimulation with appropriate cytokines induces them to differentiate into functional macrophages, osteoclasts, dendritic cells, granulocytes and natural killer cells. As expected for a clonogenic haematopoietic progenitor with lymphomyeloid developmental potential, the Pax5-/- pro-B cell expresses genes of different lineage-affiliated programmes, and restoration of Pax5 activity represses this lineage-promiscuous transcription. Pax5 therefore plays an essential role in B-lineage commitment by suppressing alternative lineage choices.
1,085 citations
TL;DR: The results indicate that all of the effects of CSF-1 are mediated via the CSf-1R, but that subtle effects of the CS fms proto-oncogene could result from its CS F-1-independent activation.
1,059 citations
"The mechanism of repression of the ..." refers background in this paper
...Expression of this growth factor receptor is crucial for macrophage differentiation and is developmentally regulated (Dai et al, 2002; Tagoh et al, 2002). c-fms is a target of the transcription factor PU.1 and is already expressed at a low level in HSCs....
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