Flowchart: Preparation: Pax5
 


                 

       

Text Box: Pax5                                            

                                     

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Text Box: C-Fms
Text Box: Rag1-Rag2
 


                                

                                                  

                                                              

                                             

                               

          V(H)     DJ(H)    

Nat Immunol. 2006 May 7; [Epub ahead of print]

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Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes.

Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD.

[1] Division of Developmental and Clinical Immunology, Birmingham, Alabama 35294, USA. [2] Department of Medicine, Birmingham, Alabama 35294, USA. [3] Department of Cell Biology, Birmingham, Alabama 35294, USA. [4] Department of Microbiology, Birmingham, Alabama 35294, USA.

Immunoglobulin rearrangement from variable heavy chain (V(H)) to diversity (D)-joining heavy chain (J(H)), which occurs exclusively in B lineage cells, is impaired in mice deficient for the B lineage-specific transcription factor Pax5. Conversely, ectopic Pax5 expression in thymocytes promotes the rearrangement of D(H)-proximal V(H)7183 genes. In exploring the mechanism for Pax5 regulation of V(H)-to-DJ(H) recombination, we have identified multiple Pax5 binding sites in the coding regions of human and mouse V(H) gene segments. Pax5 bound to those sites in vitro and occupied V(H) genes in early human and mouse B lineage cells. Moreover, Pax5 interacted with the recombination-activating gene 1 (RAG1)-RAG2 complex to enhance RAG-mediated V(H) recombination signal sequence cleavage and recombination of a V(H) gene substrate. These findings indicate a direct activating function for Pax5 in RAG-mediated immunoglobulin V(H)-to-DJ(H) recombination.

PMID: 16680144 [PubMed - as supplied by publisher]

EMBO J. 2006 Mar 8;25(5):1070-80. Epub 2006 Feb 16.

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The mechanism of repression of the myeloid-specific c-fms gene by Pax5 during B lineage restriction.

Tagoh H, Ingram R, Wilson N, Salvagiotto G, Warren AJ, Clarke D, Busslinger M, Bonifer C.

Division of Experimental Haematology, LIMM, University of Leeds, St James's University Hospital, Leeds, UK.

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