On the role of transcription in positioning nucleosomes.
On the role of transcription in positioning nucleosomes.
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DOI：
10.1371/journal.pcbi.1008556
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发表时间：
2021-01
影响因子：
4.3
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Jiang Z;Zhang B
核小体的定位对基因组的功能至关重要。虽然DNA序列在定位核小体中的作用已被很好地了解，但关于转录影响的详细机制仍缺乏了解。通过数值模拟，我们研究了核小体密度分布对多种物种转录水平的依赖关系。我们发现，酵母的低核小体亲和力，而不是小鼠，启动子有助于形成非活性基因的阶段性核小体阵列。对于活性基因来说，由两种类型的重塑酶之间的拉锯战引起的+1核小体的异质性分布对于复制它们的密度分布是必不可少的。特别是，虽然已知定位酶可以重塑+1核小体并将其与转录起始点(TSS)对齐，但使用一对核小体作为底物的间隔酶可以使核小体阵列远离TSS。这些酶之间的竞争导致两种类型的核小体密度分布，其中+1核小体定位良好和定位不良。最后，我们证明了POL II辅助组蛋白交换，如果发生得很快，可以消除重塑酶的影响。通过阐明个体因素的作用，我们的研究调和了关于转录在跨物种定位核小体方面的总体影响的似乎相互矛盾的结果。核小体定位通过调节蛋白质结合部位的可及性和高阶染色质组织，在基因组的功能中起着关键作用。虽然在研究DNA序列在核小体定位中的作用方面已经取得了重大进展，但我们对转录影响的理解还比较落后。我们的研究使用动力学模拟来探索DNA序列特异性、转录因子结合、酶重塑和POL II延伸在定位核小体中的作用。这表明，酵母和小鼠胚胎干细胞在不同转录水平下观察到的核小体密度分布的差异，可以从两种重塑酶之间的拉锯战中理解。
Nucleosome positioning is crucial for the genome’s function. Though the role of DNA sequence in positioning nucleosomes is well understood, a detailed mechanistic understanding on the impact of transcription remains lacking. Using numerical simulations, we investigated the dependence of nucleosome density profiles on transcription level across multiple species. We found that the low nucleosome affinity of yeast, but not mouse, promoters contributes to the formation of phased nucleosomes arrays for inactive genes. For the active genes, a heterogeneous distribution of +1 nucleosomes, caused by a tug-of-war between two types of remodeling enzymes, is essential for reproducing their density profiles. In particular, while positioning enzymes are known to remodel the +1 nucleosome and align it toward the transcription start site (TSS), spacer enzymes that use a pair of nucleosomes as their substrate can shift the nucleosome array away from the TSS. Competition between these enzymes results in two types of nucleosome density profiles with well- and ill-positioned +1 nucleosome. Finally, we showed that Pol II assisted histone exchange, if occurring at a fast speed, can abolish the impact of remodeling enzymes. By elucidating the role of individual factors, our study reconciles the seemingly conflicting results on the overall impact of transcription in positioning nucleosomes across species. Nucleosome positioning plays a key role in the genome’s function by regulating the accessibility of protein binding sites as well as higher-order chromatin organization. Though significant progress has been made towards studying the role of DNA sequence in positioning the nucleosomes, our understanding on the impact of transcription lags behind. Our study uses kinetic simulations to explore the role of DNA sequence specificity, transcription factor binding, enzyme remodeling, and Pol II elongation in positioning nucleosomes. It suggests that the differences in nucleosome density profiles observed at various transcription levels in yeast and mouse embryonic stem cells can be understood from a tug-of-war between two types of remodeling enzymes.
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