Index and biological spectrum of human DNase I hypersensitive sites
Index and biological spectrum of human DNase I hypersensitive sites
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DOI：
10.1038/s41586-020-2559-3
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发表时间：
2020-07-29
期刊：
影响因子：
64.8
通讯作者：
Stamatoyannopoulos, John
中科院分区：
文献类型：
--
作者：
Meuleman, Wouter;Muratov, Alexander;Stamatoyannopoulos, John
DNase I超敏位点(DHSS)是调控DNA的通用标记(1-5)，包含与疾病和表型性状相关的遗传变异(6-8)。我们从733个人类生物样本中创建了DHSS的高分辨率地图，涵盖了438个细胞和组织类型和状态，并将这些地图整合在一起，以描绘和数字索引人类基因组序列中的大约360万个DHSS，为调控DNA提供了一个通用的坐标系。在这里，我们展示了这些图谱高度分辨人类基因组的顺式调节隔间，它以非常高的密度编码出人意料的多样化的细胞和组织选择性调节程序。这些程序可以通过一个简单的词汇表全面捕获，该词汇表允许为每个国土安全部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，我们发现，急剧分解的DHSS显著增强了疾病和性状的遗传关联性和遗传力信号。我们发现，遗传信号不是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控的DHSS集上。综上所述，我们的结果为以DHSS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，并为人类基因调控的架构提供了一个新的全球视角。来自733个人类生物样本的DNase I超敏感部位的高分辨率地图被用于识别和索引人类基因组中的调控DNA。
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 thecis-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.