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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Analysis Of Intergenic Transcription And Histone Modification Across The Human Immunoglobulin Heavy-chain Locus
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Analysis Of Intergenic Transcription And Histone Modification Across The Human Immunoglobulin Heavy-chain Locus

机译：人类免疫球蛋白重链基因座的基因组转录和组蛋白修饰的分析

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Ig class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID) mediated deamination of the switch (S) regions; the resultant mismatch is processed to yield the DNA breaks required for recombination. Whereas many of the pathways involved in the mechanism of recombination have been identified, little is known about how CSR is regulated. AID action is known to require transcription of the Ig heavy-chain genes. However, it is not understood how AID is restricted to the Ig genes. Many aspects of gene expression are known to be regulated by modification of chromatin structure. In turn, chromatin is known to be regulated by several RNA-dependent activities. We have mapped the transcriptional and chromatin landscape of the human Ig heavy-chain locus to investigate the effect these activities have on CSR. We demonstrate that the Ig heavy-chain constant genes and 3'-regulatory regions are in an active chromatin conformation in unstimulated total human B cells: the locus undergoes both genic and intergenic transcription and possesses histone modifications associated with "active" chromatin (acetylated H3 and H4 and lysine 4 trimethylated H3). However, on cytokine stimulation, these modifications spread into the S regions, demonstrating a chromatin remodeling activity associated with switching. Surprisingly, after stimulation, the S regions also accumulate lysine 9 trimethylated H3, a modification previously associated with gene silencing. These data demonstrates that the Ig locus is maintained with a complex pattern of both positive and negative histone marks and suggest that some of these marks may have dual functions.
机译：通过激活诱导的胞苷脱氨酶（AID）介导的开关（S）区的脱氨作用来引发Ig类开关重组（CSR）；处理产生的错配以产生重组所需的DNA断裂。尽管已经确定了许多参与重组机制的途径，但对如何调节CSR知之甚少。已知AID作用需要Ig重链基因的转录。然而，还不了解AID如何限制于Ig基因。已知基因表达的许多方面受染色质结构修饰的调节。反过来，已知染色质受几种RNA依赖性活性的调节。我们绘制了人类Ig重链基因座的转录和染色质分布图，以研究这些活性对CSR的影响。我们证明，Ig重链恒定基因和3'调控区在未受刺激的人类B细胞中处于活跃的染色质构象：基因座经历了基因和基因间转录，并具有与“活跃”染色质（乙酰化H3）相关的组蛋白修饰和H4和赖氨酸4三甲基化的H3）。但是，在细胞因子刺激下，这些修饰扩散到S区域，表明与转换相关的染色质重塑活性。令人惊讶地，在刺激之后，S区域还积聚了赖氨酸9三甲基化的H3，这是以前与基因沉默相关的修饰。这些数据表明，Ig基因座维持有正负组蛋白标记的复杂模式，并暗示其中一些标记可能具有双重功能。

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