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J Exp Med. 2017 Jul 3;214(7):2059-2071. doi: 10.1084/jem.20160514. Epub 2017 May 31.

Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription.

Author information

1
Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
2
Department of Surgery, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
3
Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
4
Division of Molecular Immunology, Department of Internal Medicine 3 - Rheumatology and Immunology, Nikolaus-Fiebiger-Center, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
5
Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany aline.bozec@uk-erlangen.de.

Abstract

The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7-stimulated pro-B cell cultures revealed a reduced differentiation from large pre-B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2-deficient B cells. Moreover, expression of IL7Rα and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro-B cell proliferation and small pre-B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2-deficient pro-B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages.

PMID:
28566276
PMCID:
PMC5502419
DOI:
10.1084/jem.20160514
[Indexed for MEDLINE]
Free PMC Article

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