Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, but it remains challenging to distinguish variants that affect regulatory function2. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin3–6. However, only a small fraction of such sites have been precisely resolved on the human genome sequence6. Here, to enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate about 4.5 million compact genomic elements that encode transcription factor occupancy at nucleotide resolution. We map the fine-scale structure within about 1.6 million DNase I-hypersensitive sites and show that the overwhelming majority are populated by well-spaced sites of single transcription factor–DNA interaction. Cell-context-dependent cis-regulation is chiefly executed by wholesale modulation of accessibility at regulatory DNA rather than by differential transcription factor occupancy within accessible elements. We also show that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions1,7 is almost entirely attributable to variants within footprints, and that functional variants that affect transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find increased density of human genetic variation within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation. A high-density DNase I cleavage map from 243 human cell and tissue types provides a genome-wide, nucleotide-resolution map of human transcription factor footprints.

中文翻译：

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人类转录因子足迹的全球参考图谱

转录因子与调控 DNA 的组合结合是所有生物体中基因调控的基础。调控区域的遗传变异与疾病和不同的表型特征有关，但区分影响调控功能的变异仍然具有挑战性。基因组 DNase I 足迹能够对天然染色质 3-6 内转录因子占据位点进行定量、核苷酸分辨率的描绘。然而，只有一小部分此类位点已在人类基因组序列上得到精确解析。在这里，为了能够全面绘制转录因子足迹，我们从 243 种人类细胞和组织类型和状态中生成了高密度 DNase I 切割图，并将这些数据整合以描绘出大约 4 个。500 万个紧凑的基因组元素，以核苷酸分辨率编码转录因子的占有率。我们绘制了约 160 万个 DNase I 超敏位点内的精细结构，并表明绝大多数由单个转录因子-DNA 相互作用的间隔良好的位点组成。依赖于细胞环境的顺式调节主要通过调节 DNA 的可及性的大规模调节来执行，而不是通过可接近元件内的差异转录因子占有率来执行。我们还表明，与调节区域中的疾病或表型特征相关的遗传变异的富集 1,7 几乎完全归因于足迹内的变异，并且影响转录因子占用的功能变异几乎均匀地分配在损失和获得之间。功能等位基因。出乎意料的是，我们发现转录因子足迹中人类遗传变异的密度增加，揭示了顺式调控进化的一个未被重视的驱动因素。我们的结果为基因调控机制和功能性遗传变异的全局和核苷酸精度分析提供了一个框架。来自 243 种人类细胞和组织类型的高密度 DNase I 切割图提供了人类转录因子足迹的全基因组核苷酸分辨率图。