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.
Division of Experimental Haematology, LIMM, University of Leeds, St James's University Hospital, Leeds, UK.
Hiromi
H
Tagoh
Richard
R
Ingram
Nicola
N
Wilson
Giorgia
G
Salvagiotto
Alan J
AJ
Warren
Deborah
D
Clarke
Meinrad
M
Busslinger
Constanze
C
Bonifer
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