小柯机器人

科学家绘制出人类转录因子足迹的全局参考图谱
2020-08-01 23:22

近日,美国华盛顿大学John A. Stamatoyannopoulos、Jeff Vierstra等研究人员合作绘制出人类转录因子足迹的全局参考图谱。该研究于2020年7月29日发表于国际学术期刊《自然》。

为了能够全面映射转录因子的足迹,研究人员从243种人类细胞和组织的类型和状态生成了高密度DNase I剪切图谱,并整合了这些数据以描绘出约450万个紧凑的基因组元件在核苷酸分辨率下编码转录因子的占有率。研究人员绘制了约160万个DNase I超敏感位点内的精细结构图,并显示绝大多数由单个转录因子与DNA相互作用的位点组成。细胞背景依赖性顺式调节主要是通过调节DNA上可及性的整体调节来执行,而不是通过可及元件内差异转录因子的占有来执行。

研究人员还显示,与疾病或表型性状相关的遗传变异在调节区域的富集几乎完全归因于足迹内的变异,而影响转录因子占用的功能变异几乎在功能丧失和功能获得等位基因之间平均分配。出乎意料的是,研究人员发现转录因子足迹内人类遗传变异的密度增加,从而揭示了顺式调控进化的未知驱动因素。这些结果为基因调节机制和功能遗传变异的全局以及核苷酸精度的分析提供了框架。

据介绍,转录因子与调节性DNA的组合结合可参与所有生物体中的基因调节。调节区域的遗传变异与疾病和多种表型特征有关,但是区分影响调节功能的变异仍然具有挑战性。基因组DNase I足迹可实现染色质中转录因子占据位点的定量、核苷酸分辨率的绘制。但是,只有一小部分此类位点已在人类基因组序列上精确解析。

附:英文原文

Title: Global reference mapping of human transcription factor footprints

Author: Jeff Vierstra, John Lazar, Richard Sandstrom, Jessica Halow, Kristen Lee, Daniel Bates, Morgan Diegel, Douglas Dunn, Fidencio Neri, Eric Haugen, Eric Rynes, Alex Reynolds, Jemma Nelson, Audra Johnson, Mark Frerker, Michael Buckley, Rajinder Kaul, Wouter Meuleman, John A. Stamatoyannopoulos

Issue&Volume: 2020-07-29

Abstract: 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 chromatin3,4,5,6. 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.

DOI: 10.1038/s41586-020-2528-x

Source: https://www.nature.com/articles/s41586-020-2528-x

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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