title: Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4.
abstract: The transcription factor IRF4 regulates immunoglobulin class switch recombination and plasma cell differentiation. Its differing concentrations appear to regulate mutually antagonistic programs of B and plasma cell gene expression. We show IRF4 to be also required for generation of germinal center (GC) B cells. Its transient expression in vivo induced the expression of key GC genes including Bcl6 and Aicda. In contrast, sustained and higher concentrations of IRF4 promoted the generation of plasma cells while antagonizing the GC fate. IRF4 cobound with the transcription factors PU.1 or BATF to Ets or AP-1 composite motifs, associated with genes involved in B cell activation and the GC response. At higher concentrations, IRF4 binding shifted to interferon sequence response motifs; these enriched for genes involved in plasma cell differentiation. Our results support a model of "kinetic control" in which signaling-induced dynamics of IRF4 in activated B cells control their cell-fate outcomes.
authors.affiliation: Departments of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ochiai
authors.forename: Mark
authors.initials: M
authors.lastname: Maienschein-Cline
authors.forename: Giorgia
authors.initials: G
authors.lastname: Simonetti
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rosenthal
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.forename: Anita S
authors.initials: AS
authors.lastname: Chong
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Dinner
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
authors.forename: Roger
authors.initials: R
authors.lastname: Sciammas
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002454:Cell Differentiation; D003564:Cytidine Deaminase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D003564:Cytidine Deaminase; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4; C431772:Batf protein, mouse; C490010:Bcl6 protein, mouse; C490424:Pou2af1 protein, mouse; C513258:Prdm1 protein, mouse