Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation

The transcriptional repressors BCL6 and BACH2 are crucial regulators of germinal center (GC) B-cell fate, and are known to interact and repress transcription of PRDM1, a key driver of plasma cell differentiation. How these factors cooperate is not fully understood. Herein, we show that GC formation...

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Veröffentlicht in:Blood 2014-02, Vol.123 (7), p.1012-1020
Hauptverfasser: Huang, Chuanxin, Geng, Huimin, Boss, Isaac, Wang, Ling, Melnick, Ari
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Sprache:eng
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Zusammenfassung:The transcriptional repressors BCL6 and BACH2 are crucial regulators of germinal center (GC) B-cell fate, and are known to interact and repress transcription of PRDM1, a key driver of plasma cell differentiation. How these factors cooperate is not fully understood. Herein, we show that GC formation is only minimally impaired in Bcl6+/− or Bach2+/− mice, although double heterozygous Bcl6+/−Bach2+/− mice exhibit profound reduction in GC formation. Splenic B cells from Bcl6+/−Bach2+/− mice display accelerated plasmacytic differentiation and high expression of key plasma cell genes such as Prdm1, Xbp1, and CD138. Chromatin immunoprecipitation sequencing revealed that in B cells, BACH2 is mostly bound to genes together with its heterodimer partner MAFK. The BACH2-MAFK complex binds to sets of genes known to be involved in the GC response, 60% of which are also targets of BCL6. Approximately 30% of BACH2 peaks overlap with BCL6, including cis-regulatory sequences of the PRDM1 gene. BCL6 also modulates BACH2 protein stability and their protein levels are positively correlated in GC B cells. Therefore, BCL6 and BACH2 cooperate to orchestrate gene expression patterning in GC B cells through both transcriptional and biochemical mechanisms, which collectively determine the proper initiation and timing of terminal differentiation. •BCL6 and BACH2 cooperatively regulate GC B-cell development.•The cooperative action of BCL6 and BACH2 is through both transcriptional and biochemical mechanisms.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2013-07-518605