Gfi1b negatively regulates Rag expression directly and via the repression of FoxO1.
Gfi1b negatively regulates Rag expression directly and via the repression of FoxO1.
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DOI：
10.1084/jem.20110645
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发表时间：
2012-01-16
期刊：
影响因子：
--
通讯作者：
Schlissel MS
中科院分区：
文献类型：
--
作者：
Schulz D;Vassen L;Chow KT;McWhirter SM;Amin RH;Möröy T;Schlissel MS
GFI1B通过直接与RAG位点结合和抑制Foxo1来负向调节RAG的表达；缺乏Gfi1b和Gfi1的小鼠表现出B细胞发育的障碍。精确调控重组激活基因(RAG)的表达是防止RAG介导的DNA断裂引起的基因组不稳定的关键。虽然RAg激活的机制已经被很好地描述，但RAg在B细胞发育早期下调表达的机制还没有完全阐明。利用互补DNA文库筛选，我们确定转录抑制因子Gfi1b是RAG基因座的负调控因子。Gfi1b的表达导致Rag1和Rag2在细胞系和原代小鼠细胞中的抑制。相反，Gfi1b缺陷的细胞系表现出RAG表达增加，双链断裂和重组，以及细胞周期缺陷。在原代细胞中，Gfi1b的转录与RAG转录呈负相关，Gfi1和Gfi1b的同时失活导致B细胞发育早期RAg转录的增加。此外，体内Gfi1和Gfi1b的缺失会严重阻碍B细胞的发育。GFI1B通过双重机制协调RAG抑制。Gfi1b直接结合到B细胞特异性Erag增强子的5‘位导致RAG基因座的表观遗传变化，而间接抑制是通过抑制反式激活剂Foxo1实现的。总之，我们的实验表明，GFI家族成员是正常B细胞发育所必需的，并在调节V(D)J重组酶的表达方面发挥重要作用。
Gfi1b negatively regulates Rag expression through direct binding to the Rag locus and through inhibition of Foxo1; mice lacking both Gfi1b and Gfi1 exhibit a block in B cell development. Precise regulation of Rag (recombination-activating gene) expression is crucial to prevent genomic instability caused by the generation of Rag-mediated DNA breaks. Although mechanisms of Rag activation have been well characterized, the mechanism by which Rag expression is down-regulated in early B cell development has not been fully elucidated. Using a complementary DNA library screen, we identified the transcriptional repressor Gfi1b as negative regulator of the Rag locus. Expression of Gfi1b causes repression of Rag1 and Rag2 in cell lines and primary mouse cells. Conversely, Gfi1b-deficient cell lines exhibit increased Rag expression, double-strand breaks and recombination, and cell cycle defects. In primary cells, transcription of Gfi1b inversely correlates with Rag transcription, and simultaneous inactivation of Gfi1 and Gfi1b leads to an increase in Rag transcription early in B cell development. In addition, deletion of Gfi1 and Gfi1b in vivo results in a severe block in B cell development. Gfi1b orchestrates Rag repression via a dual mechanism. Direct binding of Gfi1b to a site 5′ of the B cell–specific Erag enhancer results in epigenetic changes in the Rag locus, whereas indirect inhibition is achieved through repression of the trans-activator Foxo1. Together, our experiments show that Gfi family members are essential for normal B cell development and play an important role in modulating expression of the V(D)J recombinase.
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