EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop.
EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop.
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DOI：
10.1038/s41467-017-01029-x
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发表时间：
2017-10-12
影响因子：
16.6
通讯作者：
Melnick AM
中科院分区：
文献类型：
--
作者：
Béguelin W;Rivas MA;Calvo Fernández MT;Teater M;Purwada A;Redmond D;Shen H;Challman MF;Elemento O;Singh A;Melnick AM
EZH 2组蛋白甲基转移酶是B细胞形成生发中心（GC）所必需的。我们发现EZH 2通过抑制细胞周期蛋白依赖性激酶抑制剂CDKN 1A（p21 Cip 1）介导GC的形成。Cdkn 1a的缺失拯救了Ezh 2 −/−小鼠中的GC反应。使用模拟GC反应的3D B细胞滤泡类器官系统，我们表明EZH 2的耗尽以Cdkn 1a依赖的方式抑制GC B细胞的G1至S期转变。Cdkn 1a −/− Ezh 2 −/−小鼠的GC B细胞具有高水平的磷酸化Rb，表明Cdkn 1a的缺失使细胞周期进展。此外，转录因子E2 F1在GC反应期间诱导EZH 2。E2 f1 −/−小鼠表现出受损的GC反应，通过恢复EZH 2表达来挽救，从而定义了一个正反馈回路，其中EZH 2通过抑制CDKN 1A来控制GC B细胞增殖，使细胞周期进展伴随Rb的磷酸化和E2 F1的释放。组蛋白甲基转移酶EZH 2通过产生H3 K27 me 3标记使基因沉默。在这里，作者使用3D GC类器官并显示EZH 2通过CDKN 1A的表观遗传沉默和细胞周期检查点的释放介导生发中心（GC）的形成。
The EZH2 histone methyltransferase is required for B cells to form germinal centers (GC). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A (p21Cip1). Deletion of Cdkn1a rescues the GC reaction in Ezh2 −/− mice. Using a 3D B cell follicular organoid system that mimics the GC reaction, we show that depletion of EZH2 suppresses G1 to S phase transition of GC B cells in a Cdkn1a-dependent manner. GC B cells of Cdkn1a −/− Ezh2 −/− mice have high levels of phospho-Rb, indicating that loss of Cdkn1a enables progression of cell cycle. Moreover, the transcription factor E2F1 induces EZH2 during the GC reaction. E2f1 −/− mice manifest impaired GC responses, which is rescued by restoring EZH2 expression, thus defining a positive feedback loop in which EZH2 controls GC B cell proliferation by suppressing CDKN1A, enabling cell cycle progression with a concomitant phosphorylation of Rb and release of E2F1. The histone methyltransferase EZH2 silences genes by generating H3K27me3 marks. Here the authors use a 3D GC organoid and show EZH2 mediates germinal centre (GC) formation through epigenetic silencing of CDKN1A and release of cell cycle checkpoints.
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