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J. Biol. Chem., Vol. 281, Issue 50, 38226-38234, December 15, 2006

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Plasmacytic Transcription Factor Blimp-1 Is Repressed by Bach2 in B Cells^*

Kyoko Ochiai¹, Yasutake Katoh, Tsuyoshi Ikura, Yutaka Hoshikawa^¶, Tetsuo Noda^¶, Hajime Karasuyama^||, Satoshi Tashiro, Akihiko Muto, and Kazuhiko Igarashi²

From the Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan, Research Institution for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Hiroshima 734-8551, Japan, the ^¶Japanese Foundation for Cancer Research, Cancer Institute, Ariake 3-10-6, Tokyo 135-8550, Japan, and the ^||Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan

Bach2 is a B cell-specific transcription repressor whose deficiency in mice causes a reduced class switch recombination and a reduced somatic hypermutation of immunoglobulin genes. Little is known about the direct target genes of Bach2 in B cells. By analyzing various B cell and plasma cell lines, we showed that the expression patterns of Bach2 and Blimp-1 (B lymphocyte-induced maturation protein 1), a master regulator of plasma cell differentiation, are mutually exclusive. The reporter gene of the Blimp-1 gene (Prdm1) was repressed by the overexpression of Bach2 in B cell lines. The heterodimer of Bach2/MafK bound to the Maf recognition element located upstream of the Prdm1 promoter in an electrophoretic mobility shift assay. The binding of MafK in B cells to the Prdm1 Maf recognition element was confirmed by chromatin immunoprecipitation assays. When MafK was purified from the BAL17 B cell line, a significant portion of it was present as a heterodimer with Bach2, with no apparent formation of MafK homodimer. These results strongly suggest that Bach2 represses the expression of Blimp-1 together with MafK in B cells prior to plasma cell differentiation. Accordingly, the knockdown of Bach2 mRNA using short hairpin RNA in BAL17 cells resulted in higher levels of Prdm1 expression after the stimulation of B cell receptor by surface IgM cross-linking. Induction of Prdm1 was more robust and faster in primary Bach2-deficient B cells than in wild-type control B cells upon lipopolysaccharide stimulation. Therefore, the Prdm1 regulation in B cells involves the repression by Bach2, which may be cancelled upon terminal plasma cell differentiation.

Received for publication, August 9, 2006 , and in revised form, September 25, 2006.

^* This work was supported by grants-in-aid from the Ministry of Education, Science, Sport, and Culture of Japan and by the Astellas Foundation for Research on Metabolic Disorders, the Uehara Memorial Foundation, and Takeda Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Hiroshima University 21st century COE program.

² To whom correspondence should be addressed: Dept. of Biochemistry, Tohoku University School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan. Tel.: 81-22-717-7595; Fax: 81-22-717-7598; E-mail: igarak{at}mail.tains.tohoku.ac.jp.

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