Analysis of intergenic transcription and histone modification across the human immunoglobulin heavy-chain locus
Analysis of intergenic transcription and histone modification across the human immunoglobulin heavy-chain locus
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DOI：
10.1073/pnas.0808462105
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发表时间：
2008-10-14
影响因子：
11.1
通讯作者：
Fear, David J.
中科院分区：
文献类型：
--
作者：
Chowdhury, Muslima;Forouhi, Omid;Fear, David J.
IG类开关重组（CSR）由激活诱导的胞苷脱氨酶（AID）介导的开关（S）区域脱氨基作用引发;处理所得错配以产生重组所需的DNA断裂。虽然许多参与重组机制的途径已被确定，但对CSR如何调节知之甚少。已知AID作用需要IG重链基因的转录。然而，还不清楚AID是如何被限制在IG基因上的。已知基因表达的许多方面通过染色质结构的修饰来调节。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图谱，以研究这些活动对CSR的影响。我们证明，在未受刺激的总人B细胞中，IG重链恒定基因和3 '调控区处于活性染色质构象：该位点经历基因和基因间转录，并具有与“活性”染色质相关的组蛋白修饰（乙酰化H3和H4以及赖氨酸4三甲基化H3）。然而，在细胞因子刺激下，这些修饰扩散到9个区域，证明了与转换相关的染色质重塑活性。令人惊讶的是，在刺激后，S区也积累赖氨酸9三甲基化H3，一种先前与基因沉默相关的修饰。这些数据表明，IG基因座保持了复杂的模式，积极和消极的组蛋白标记，并建议这些标记中的一些可能具有双重功能。
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 9 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.