CAG/CTG repeats alter the affinity for the histone core and the positioning of DNA in the nucleosome.
CAG/CTG repeats alter the affinity for the histone core and the positioning of DNA in the nucleosome.
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DOI：
10.1021/bi301416v
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发表时间：
2012-12-11
期刊：
影响因子：
2.9
通讯作者：
Delaney S
中科院分区：
文献类型：
--
作者：
Volle CB;Delaney S
三核苷酸重复序列（TNR）存在于整个基因组中，并且它们的扩增与几种神经退行性疾病（包括亨廷顿病）有关。已经使用寡核苷酸和质粒研究了TNR;然而，对重复DNA如何响应基因组包装知之甚少。在这里，我们调查的行为CAG/CTG重复纳入核小体核心颗粒，染色质包装的最基本的单位。为了评估CAG/CTG重复序列和组蛋白核心之间的一般相互作用，我们确定了各种含TNR的DNA底物形成核小体的效率，揭示了即使是短的CAG/CTG片段也是稳健的扩增剂。然而，亨廷顿基因侧翼序列（htt）的存在降低了掺入。酶和化学探针显示，无论侧翼序列如何，随着CAG/CTG重复序列数量的增加，核小体中DNA的重新定位。值得注意的是，重复序列的周期性作为长度的函数保持不变，并且始终为每螺旋圈10.7个碱基对。相比之下，非重复侧翼序列的周期性变化，并且小于重复区，每转约10.0-10.5个碱基对。此外，虽然CAG/CTG重复序列在核小体中保持为典型双链体，但核小体形成导致htt基因中由CCG/CGG重复序列组成的二级重复序列区中的扭结。这项工作突出了CAG/CTG重复序列在核小体中整合和定位的先天能力，以及这种行为如何受到htt侧翼序列的调节。此外，它还阐明了基因组内健康和患病长度重复序列包装的差异。
Trinucleotide repeats (TNRs) occur throughout the genome and their expansion has been linked to several neurodegenerative disorders, including Huntington’s Disease. TNRs have been studied using both oligonucleotides and plasmids; however, less is know about how repetitive DNA responds to genomic packaging. Here, we investigate the behavior of CAG/CTG repeats incorporated into nucleosome core particles, the most basic unit of chromatin packaging. To assess the general interaction between CAG/CTG repeats and the histone core, we determined the efficiency with which various TNR-containing DNA substrates form nucleosomes, revealing that even short CAG/CTG tracts are robust incorporators. However, presence of the Huntingtin gene flanking sequence (htt) decreases incorporation. Enzymatic and chemical probing revealed repositioning of the DNA in the nucleosome as the number of CAG/CTG repeats increased, regardless of the flanking sequence. Notably, the periodicity of the repeat tract remained unchanged as a function of length and is consistently 10.7 base pairs per helical turn. In contrast, the periodicity of the non-repetitive flanking sequence varies, and is smaller than the repeat tract at ~10.0–10.5 base pairs per turn. Furthermore, while the CAG/CTG repeats remain as canonical duplex in the nucleosome, nucleosome formation causes kinking in a secondary repeat tract in the htt gene, comprised of CCG/CGG repeats. This work highlights the innate ability of CAG/CTG repeats to incorporate and to position in nucleosomes and how that behavior is modulated by the htt flanking sequence. In addition, it illuminates the differences in packaging of healthy and diseased length repeat tracts within the genome.
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