The mechanism of repression of the myeloid-specific c-fms gene by Pax5 during B lineage restriction.
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.
Tagoh
Hiromi
H
Division of Experimental Haematology, LIMM, University of Leeds, St James's University Hospital, Leeds, UK.
Ingram
Richard
R
Wilson
Nicola
N
Salvagiotto
Giorgia
G
Warren
Alan J
AJ
Clarke
Deborah
D
Busslinger
Meinrad
M
Bonifer
Constanze
C
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D019070:Cell Lineage; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D018983:DNA Footprinting; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
D002843:Chromatin; D003850:Deoxyribonuclease I; D051757:PAX5 Transcription Factor; D011518:Proto-Oncogene Proteins; D012319:RNA Polymerase II; D016186:Receptor, Macrophage Colony-Stimulating Factor; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C497282:Pax5 protein, mouse