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首页> 外文期刊>Molecular and Cellular Biology >E2A and IRF-4/Pip Promote Chromatin Modification and Transcription of the Immunoglobulin κ Locus in Pre-B Cells
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E2A and IRF-4/Pip Promote Chromatin Modification and Transcription of the Immunoglobulin κ Locus in Pre-B Cells

机译：E2A和IRF-4 / Pip促进前B细胞中免疫球蛋白κ基因座的染色质修饰和转录

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The immunoglobulin kappa light chain (Igκ) locus is regulated in a lineage- and stage-specific manner during B-cell development. The highly restricted timing of V to J gene recombination at the pre-B-cell stage is under the control of two enhancers, the intronic enhancer (κEi) and the 3′ enhancer (κE3′), flanking the constant exon. E2A transcription factors have been indicated to be directly involved in the regulation of Igκ locus activation. In this study, we utilize E2A-deficient pre-B cells to directly investigate the mechanism of E2A-mediated Igκ activation. We demonstrate that Igκ germ line transcription is severely impaired and recombination is blocked in the absence of E2A. Reconstitution of E2A?/? pre-B cells with inducible human E2A (E47R) is sufficient to promote chromatin modification of Igκ and rescue Igκ germ line transcription and Jκ gene recombinase accessibility. Furthermore, we show that increased E2A recruitment to κEi and κE3′ correlates with activation of Igκ in pre-B cells and that recruitment of E2A to κE3′ is in part dependent on the transcription factor IRF-4. Inhibition of IRF-4 expression in pre-B cells leads to a significant reduction of Igκ germ line transcription and enhancer acetylation. In the absence of E2A, increased IRF-4 expression is not sufficient to promote Igκ enhancer chromatin modification or transcription, suggesting that the sequential involvement of IRF-4 and E2A is necessary for the activation of the Igκ locus. Finally, we provide genetic evidence in the mouse that E2A gene dosage can influence the development of pre-B cells during the phase of Igκ gene activation.
机译：免疫球蛋白κ轻链（Igκ）基因座在B细胞发育过程中以谱系和阶段特异性方式调节。在前B细胞阶段，V到J基因重组的高度受时间限制在两个增强子的控制下，内含子增强子（κEi）和3'增强子（κE3'）位于恒定外显子的两侧。已经表明E2A转录因子直接参与Igκ基因座激活的调节。在这项研究中，我们利用E2A缺陷的pre-B细胞直接研究E2A介导的Igκ激活的机制。我们证明，在没有E2A的情况下，Igκ种系转录严重受损，并且重组被阻断。用诱导型人E2A（E47R）重建 E2A ？/？ pre-B细胞足以促进Igκ的染色质修饰并拯救Igκ生殖系转录和Jκ基因重组酶可及性。此外，我们显示增加的E2A募集到κEi和κE3'与pre-B细胞中Igκ的激活相关，并且E2A募集到κE3'的过程部分取决于转录因子IRF-4。前B细胞中IRF-4表达的抑制导致Igκ生殖系转录的显着减少和增强剂乙酰化。在没有E2A的情况下，增加的IRF-4表达不足以促进Igκ增强子染色质的修饰或转录，这表明IRF-4和E2A的顺序介入对于激活Igκ基因座是必需的。最后，我们在小鼠中提供了遗传证据，证明 E2A 基因剂量可以在Igκ基因激活阶段影响pre-B细胞的发育。

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