转录起始位点上下游核小体统计定位的屏障核小体模型的定量检验
Quantitative test of the barrier nucleosome model for statistical positioning of nucleosomes up- and downstream of transcription start sites
摘要：
核小体在真核生物基因组中的位置决定了DNA序列的哪些部分容易被调节蛋白质接近，哪些不容易。核小体位置的全基因组图谱揭示了转录起始位点周围的显著模式，涉及无核小体区（NFR），两侧是平均核小体密度的显著周期性模式。虽然周期性图案清楚地反映了定位良好的核小体，但定位机制不太清楚。Mavrich等人最近的一项实验研究认为，在S.酿酒酵母是定性一致的“屏障核小体模型”，其中的振荡模式是由统计定位机制的Kornberg和Stryer。另一方面，有明确的证据表明核小体的内在序列偏好，目前还不清楚这些序列偏好在多大程度上影响观察到的模式。为了测试屏障核小体模型，我们定量分析了NFR上游和下游的酵母核小体定位数据。我们的分析是基于统计物理的Tonks模型，该模型量化了核小体的排斥体积相互作用及其位置熵之间的相互作用。我们发现，虽然NFR两侧的典型图案不同，但它们都是由相同的物理模型定量描述的，具有相同的参数，但不同的边界条件。推断的边界条件表明，NFR下游的第一个核小体（+1核小体）通常直接定位，而上游的第一个核小体通过核小体排斥DNA区域在统计学上定位。这些边界条件可以局部编码到基因组序列中，显著地塑造了核小体在每侧高达~1000 bp范围内的统计分布。
英文摘要：
The positions of nucleosomes in eukaryotic genomes determine which parts of the DNA sequence are readily accessible for regulatory proteins and which are not. Genome-wide maps of nucleosome positions have revealed a salient pattern around transcription start sites, involving a nucleosome-free region (NFR) flanked by a pronounced periodic pattern in the average nucleosome density. While the periodic pattern clearly reflects well-positioned nucleosomes, the positioning mechanism is less clear. A recent experimental study by Mavrich et al. argued that the pattern observed in S. cerevisiae is qualitatively consistent with a `barrier nucleosome model', in which the oscillatory pattern is created by the statistical positioning mechanism of Kornberg and Stryer. On the other hand, there is clear evidence for intrinsic sequence preferences of nucleosomes, and it is unclear to what extent these sequence preferences affect the observed pattern. To test the barrier nucleosome model, we quantitatively analyze yeast nucleosome positioning data both up- and downstream from NFRs. Our analysis is based on the Tonks model of statistical physics which quantifies the interplay between the excluded-volume interaction of nucleosomes and their positional entropy. We find that although the typical patterns on the two sides of the NFR are different, they are both quantitatively described by the same physical model, with the same parameters, but different boundary conditions. The inferred boundary conditions suggest that the first nucleosome downstream from the NFR (the +1 nucleosome) is typically directly positioned while the first nucleosome upstream is statistically positioned via a nucleosome-repelling DNA region. These boundary conditions, which can be locally encoded into the genome sequence, significantly shape the statistical distribution of nucleosomes over a range of up to ~1000 bp to each side.
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