Common fragile sites are characterized by histone hypoacetylation.
Common fragile sites are characterized by histone hypoacetylation.
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DOI：
10.1093/hmg/ddp410
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发表时间：
2009-12-01
影响因子：
3.5
通讯作者：
Le Beau MM
中科院分区：
文献类型：
--
作者：
Jiang Y;Lucas I;Young DJ;Davis EM;Karrison T;Rest JS;Le Beau MM
常见的脆性位点(CFS)代表了人类基因组中很大的高度不稳定的区域。CFS序列对复制的扰动很敏感；然而，CFSS不稳定性的分子基础却知之甚少。我们假设，一种独特的表观遗传模式可能是CFS对复制干扰的异常敏感性的基础。为了验证这一假设，我们分析了六个断裂程度最高的人CFS及其周围的非脆性区域(NCFS)中的染色质修饰模式。在所分析的大多数CFSS中，染色质的组蛋白乙酰化程度明显低于其周围的NCFS。曲古菌素A和/或5-氮杂脱氧胞苷处理可减少CFSS的染色体断裂。此外，最常见表达的CFs的染色质，FRA3B，比侧翼的非脆弱序列对微球菌核酸酶更具抗性。这些结果表明，组蛋白低乙酰化是CFSs特有的表观遗传模式，CFSs内的染色质可能比NCFSs内的染色质更紧密，这表明染色质构象在CFSs基因组不稳定性中发挥了作用。此外，CFSS缺乏组蛋白乙酰化可能是CFSS对复制应激特征的缺陷反应，导致该区域的遗传不稳定特征。
Common fragile sites (CFSs) represent large, highly unstable regions of the human genome. CFS sequences are sensitive to perturbation of replication; however, the molecular basis for the instability at CFSs is poorly understood. We hypothesized that a unique epigenetic pattern may underlie the unusual sensitivity of CFSs to replication interference. To examine this hypothesis, we analyzed chromatin modification patterns within the six human CFSs with the highest levels of breakage, and their surrounding non-fragile regions (NCFSs). Chromatin at most of the CFSs analyzed has significantly less histone acetylation than that of their surrounding NCFSs. Trichostatin A and/or 5-azadeoxycytidine treatment reduced chromosome breakage at CFSs. Furthermore, chromatin at the most commonly expressed CFS, the FRA3B, is more resistant to micrococcal nuclease than that of the flanking non-fragile sequences. These results demonstrate that histone hypoacetylation is a characteristic epigenetic pattern of CFSs, and chromatin within CFSs might be relatively more compact than that of the NCFSs, indicating a role for chromatin conformation in genomic instability at CFSs. Moreover, lack of histone acetylation at CFSs may contribute to the defective response to replication stress characteristic of CFSs, leading to the genetic instability characteristic of this regions.
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影响因子：
7
作者：
Bieda, M;Xu, XQ;Farnham, PJ
通讯作者：
Farnham, PJ
影响因子：
14.9
作者：
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DOI：
10.1073/pnas.95.14.8141
发表时间：
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作者：
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通讯作者：
Le Beau, Michelle M.