<br>人类 DNase I 超敏位点的索引和生物谱,Nature

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人类 DNase I 超敏位点的索引和生物谱
Nature ( IF 50.5 ) Pub Date : 2020-07-29 , DOI: 10.1038/s41586-020-2559-3
Wouter Meuleman ₁ , Alexander Muratov ₁ , Eric Rynes ₁ , Jessica Halow ₁ , Kristen Lee ₁ , Daniel Bates ₁ , Morgan Diegel ₁ , Douglas Dunn ₁ , Fidencio Neri ₁ , Athanasios Teodosiadis ₁ , Alex Reynolds ₁ , Eric Haugen ₁ , Jemma Nelson ₁ , Audra Johnson ₁ , Mark Frerker ₁ , Michael Buckley ₁ , Richard Sandstrom ₁ , Jeff Vierstra ₁ , Rajinder Kaul ₁ , John Stamatoyannopoulos _{1,

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Affiliation

DNase I 超敏位点（DHS）是调节 DNA 1 – 5 的通用标志物，包含与疾病和表型性状 6 – 8 相关的遗传变异。我们从 733 个人类生物样本（包括 438 种细胞和组织类型和状态）中创建了高分辨率的 DHS 图谱，并将它们整合在一起，以描绘和数字索引人类基因组序列中大约 360 万个 DHS，为调节 DNA 提供了一个通用的坐标系。在这里，我们表明这些图谱高度解析了人类基因组的顺式调控区室，它以非常高的密度编码出乎意料的多样化细胞和组织选择性调控程序。这些程序可以通过一个简单的词汇表全面捕获，该词汇表能够为每个 DHS 分配一个封装其组织表现的调节条形码，并以与基因表达正交的方式对蛋白质编码和非编码 RNA 基因进行全局注释。最后，我们表明，锐分的 DHS 显着增强了疾病和性状的遗传关联和遗传性信号。我们发现遗传信号不局限于少数远端元件或启动子，而是聚集在装饰整个基因体的一致调节的 DHS 集上。总之，我们的结果为以 DHS 标记的人类调控 DNA 创建了一个通用的、可扩展的坐标系和词汇表，并为人类基因调控的结构提供了新的全球视角。来自 733 个人类生物样本的 DNase I 超敏位点的高分辨率图谱用于识别和标定人类基因组内的调节 DNA。

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Index and biological spectrum of human DNase I hypersensitive sites

DNase I hypersensitive sites (DHSs) are generic markers of regulatory DNA 1 – 5 and contain genetic variations associated with diseases and phenotypic traits 6 – 8 . We created high-resolution maps of DHSs from 733 human biosamples encompassing 438 cell and tissue types and states, and integrated these to delineate and numerically index approximately 3.6 million DHSs within the human genome sequence, providing a common coordinate system for regulatory DNA. Here we show that these maps highly resolve the cis -regulatory compartment of the human genome, which encodes unexpectedly diverse cell- and tissue-selective regulatory programs at very high density. These programs can be captured comprehensively by a simple vocabulary that enables the assignment to each DHS of a regulatory barcode that encapsulates its tissue manifestations, and global annotation of protein-coding and non-coding RNA genes in a manner orthogonal to gene expression. Finally, we show that sharply resolved DHSs markedly enhance the genetic association and heritability signals of diseases and traits. Rather than being confined to a small number of distal elements or promoters, we find that genetic signals converge on congruently regulated sets of DHSs that decorate entire gene bodies. Together, our results create a universal, extensible coordinate system and vocabulary for human regulatory DNA marked by DHSs, and provide a new global perspective on the architecture of human gene regulation. High-resolution maps of DNase I hypersensitive sites from 733 human biosamples are used to identify and index regulatory DNA within the human genome.

更新日期：2020-07-29

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