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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / metabolism*
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Cell Lineage*
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Chromatin / metabolism
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Chromatin Immunoprecipitation
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DNA Footprinting
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Deoxyribonuclease I / metabolism
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Gene Expression Regulation*
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Mice
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Mice, Knockout
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Myeloid Cells / cytology
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Myeloid Cells / metabolism*
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PAX5 Transcription Factor / genetics
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PAX5 Transcription Factor / physiology*
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Promoter Regions, Genetic
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Protein Binding
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA Polymerase II
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Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors
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Receptor, Macrophage Colony-Stimulating Factor / genetics*
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Response Elements / genetics
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / metabolism
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Transcription Initiation Site
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Transcription, Genetic
Substances
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Chromatin
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PAX5 Transcription Factor
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Pax5 protein, mouse
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Proto-Oncogene Proteins
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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proto-oncogene protein Spi-1
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Receptor, Macrophage Colony-Stimulating Factor
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RNA Polymerase II
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Deoxyribonuclease I