Human BSAP and BLIMP1 conform an autoregulatory feedback loop.
B-lymphocyte-induced maturation protein-1 (BLIMP1), encoded by the PRDM1 gene, is a transcriptional repressor considered a master regulator that is required and sufficient for plasma cell (PC) differentiation. BLIMP1 represses the PAX5 gene, coding for the B-cell lineage-specific activator protein (BSAP), which is required for B-cell identity and survival. Mutations in PAX5 gene as well as in PRDM1 gene have been recently implicated in lymphomas. In the present study, sequence analysis of PRDM1 gene revealed a binding site for BSAP transcription factor. By analyzing different human cell lines, we have found that a specific nuclear factor for B-cell lines binds to a site on the PRDM1 promoter. Electrophoretic mobility shift assays identified this factor as BSAP, and chromatin immunoprecipitation assays confirmed its binding in vivo to the human PRDM1 promoter. Moreover, by ectopically expressing BSAP, and using a PRDM1 promoter with the BSAP-binding site mutated, we demonstrated that this factor represses the expression of BLIMP1. Therefore, repression of PRDM1 by BSAP reveals an autoregulatory negative-feedback loop that could play a relevant role in controlling human PC differentiation.
Unidad de Investigación, Hospital Universitario Puerta del Mar, Avenida Ana de Viya 21, 11009 Cádiz, Spain.
Francisco
F
Mora-López
Elena
E
Reales
José A
JA
Brieva
Antonio
A
Campos-Caro
D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D051757:PAX5 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D010950:Plasma Cells / Q000166:cytology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1