title: Downregulation of FOXP1 is required during germinal center B-cell function.
abstract: B-cell maturation and germinal center (GC) formation are dependent on the interplay between BCL6 and other transcriptional regulators. FOXP1 is a transcription factor that regulates early B-cell development, but whether it plays a role in mature B cells is unknown. Analysis of human tonsillar B-cell subpopulations revealed that FOXP1 shows the opposite expression pattern to BCL6, suggesting that FOXP1 regulates the transition from resting follicular B cell to activated GC B cell. Chromatin immunoprecipitation-on-chip and gene expression assays on B cells indicated that FOXP1 acts as a transcriptional activator and repressor of genes involved in the GC reaction, half of which are also BCL6 targets. To study FOXP1 function in vivo, we developed transgenic mice expressing human FOXP1 in lymphoid cells. These mice exhibited irregular formation of splenic GCs, showing a modest increase in naïve and marginal-zone B cells and a significant decrease in GC B cells. Furthermore, aberrant expression of FOXP1 impaired transcription of noncoding γ1 germline transcripts and inhibited efficient class switching to the immunoglobulin G1 isotype. These studies show that FOXP1 is physiologically downregulated in GC B cells and that aberrant expression of FOXP1 impairs mechanisms triggered by B-cell activation, potentially contributing to B-cell lymphomagenesis.
authors.affiliation: Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Ainara
authors.initials: A
authors.lastname: Sagardoy
authors.forename: Jose I
authors.initials: JI
authors.lastname: Martinez-Ferrandis
authors.forename: Sergio
authors.initials: S
authors.lastname: Roa
authors.forename: Karen L
authors.initials: KL
authors.lastname: Bunting
authors.forename: María Angela
authors.initials: MA
authors.lastname: Aznar
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.forename: Lorena
authors.initials: L
authors.lastname: Fontán
authors.forename: Vicente
authors.initials: V
authors.lastname: Fresquet
authors.forename: Ignacio
authors.initials: I
authors.lastname: Perez-Roger
authors.forename: Eloy F
authors.initials: EF
authors.lastname: Robles
authors.forename: Linde
authors.initials: L
authors.lastname: De Smedt
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Climent
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology; D006801:Humans; D008223:Lymphoma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D014066:Palatine Tonsil / Q000166:cytology; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology
chemical_list: C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins