Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation
Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation
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DOI：
10.1182/blood-2013-07-518605
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发表时间：
2014-02-13
期刊：
影响因子：
20.3
通讯作者：
Melnick, Ari
中科院分区：
文献类型：
--
作者：
Huang, Chuanxin;Geng, Huimin;Melnick, Ari
转录抑制因子BCL6和BACH2是生发中心（GC） b细胞命运的关键调节因子，已知它们相互作用并抑制PRDM1的转录，而PRDM1是浆细胞分化的关键驱动因子。这些因素是如何相互作用的尚不完全清楚。本研究表明，尽管双杂合Bcl6(+/-) Bach2（+/-）小鼠的GC形成明显减少，但Bcl6（+/-）或Bach2（+/-）小鼠的GC形成仅受到最小程度的损害。Bcl6(+/-) Bach2（+/-）小鼠脾B细胞表现出浆细胞分化加速和关键浆细胞基因如Prdm1、Xbp1和CD138的高表达。染色质免疫沉淀测序显示，在B细胞中，BACH2主要与其异源二聚体伴侣MAFK结合在一起。BACH2-MAFK复合物与已知参与GC反应的一系列基因结合，其中60%也是BCL6的靶标。大约30%的BACH2峰与BCL6重叠，包括PRDM1基因的顺式调控序列。BCL6也调节BACH2蛋白的稳定性，两者蛋白水平在GC B细胞中呈正相关。因此，BCL6和BACH2通过转录和生化机制共同协调GC B细胞的基因表达模式，共同决定终端分化的正确起始和时机。
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.