A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters.
A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters.
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DOI：
10.1016/j.celrep.2013.06.016
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发表时间：
2013-08-15
期刊：
影响因子：
8.8
通讯作者：
Melnick A
中科院分区：
文献类型：
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作者：
Hatzi K;Jiang Y;Huang C;Garrett-Bakelman F;Gearhart MD;Giannopoulou EG;Zumbo P;Kirouac K;Bhaskara S;Polo JM;Kormaksson M;MacKerell AD Jr;Xue F;Mason CE;Hiebert SW;Prive GG;Cerchietti L;Bardwell VJ;Elemento O;Melnick A
BCL6转录抑制因子是生发中心（GC） b细胞和弥漫性大b细胞淋巴瘤（DLBCL）发展所必需的。虽然BCL6可以募集多种协同抑制因子，但其在正常和恶性b细胞中的转录抑制机制尚不清楚。我们发现，在b细胞中，BCL6主要通过两种独立的机制发挥作用，这两种机制对GC和DLBCL的形成至关重要，都是通过其n端BTB结构域介导的。它们是：i)在启动子处形成独特的bcr - smrt三联体，每个辅抑制子结合到BCL6同型二聚体的对称位点，与特定的表观遗传染色质特征相关联；ii)通过smrt依赖的H3K27去乙酰化，将活性增强子“切换”为平衡但不被删除的构象，该构象由HDAC3介导，由p300组蛋白乙酰转移酶反对。增强子的动态切换为b细胞响应信号或环境线索进行快速转录和表型变化提供了基础。
The BCL6 transcriptional repressor is required for development of germinal center (GC) B-cells and diffuse large B-cell lymphomas (DLBCL). Although BCL6 can recruit multiple corepressors, its transcriptional repression mechanism of action in normal and malignant B-cells is unknown. We find that in B-cells, BCL6 mostly functions through two independent mechanisms that are collectively essential to GC formation and DLBCL, both mediated through its N-terminal BTB domain. These are: i) formation of a unique ternary BCOR-SMRT complex at promoters with each corepressor binding to symmetrical sites on BCL6 homodimers, linked to specific epigenetic chromatin features, and ii) the “toggling” of active enhancers to a poised but not erased conformation through SMRT-dependent H3K27 de-acetylation, which is mediated by HDAC3 and opposed by p300 histone acetyltransferase. Dynamic toggling of enhancers provides a basis for B-cells to undergo rapid transcriptional and phenotypic changes in response to signaling or environmental cues.