High-throughput characterization of the role of non-B DNA motifs on promoter function
High-throughput characterization of the role of non-B DNA motifs on promoter function
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DOI：
10.1016/j.xgen.2022.100111
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发表时间：
2022-04-13
期刊：
影响因子：
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通讯作者：
Ahituv, Nadav
中科院分区：
文献类型：
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作者：
Georgakopoulos-Soares, Ilias;Victorino, Jesus;Ahituv, Nadav
替代DNA构象，称为非B DNA结构，可以影响转录，但其潜在的机制和功能的影响还没有系统的特点。在这里，我们使用计算基因组分析加上大规模并行报告分析（MPRA），以显示某些非B DNA结构对基因表达有实质性的影响。基因组分析发现，在启动子的非B DNA结构港的种系变异体过量。多个MPRAs，包括一个启动子库专门设计来扰乱非B DNA结构的分析，功能验证，Z-DNA可以显着影响启动子活性。我们还观察到，非B DNA基序的生物物理性质，如Z-DNA基序的长度和G-四链体结构相对于转录方向的方向，对启动子活性有显着的影响。结合起来，它们的较高突变率和对转录的功能影响暗示了非B DNA基序的子集是人类基因表达相关表型的主要驱动因素。
Alternative DNA conformations, termed non-B DNA structures, can affect transcription, but the underlying mechanisms and their functional impact have not been systematically characterized. Here, we used compu-tational genomic analyses coupled with massively parallel reporter assays (MPRAs) to show that certain non -B DNA structures have a substantial effect on gene expression. Genomic analyses found that non-B DNA structures at promoters harbor an excess of germline variants. Analysis of multiple MPRAs, including a pro-moter library specifically designed to perturb non-B DNA structures, functionally validated that Z-DNA can significantly affect promoter activity. We also observed that biophysical properties of non-B DNA motifs, such as the length of Z-DNA motifs and the orientation of G-quadruplex structures relative to transcriptional direction, have a significant effect on promoter activity. Combined, their higher mutation rate and functional effect on transcription implicate a subset of non-B DNA motifs as major drivers of human gene-expression -associated phenotypes.