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研究揭示人类增强子和启动子序列的相容性规则
作者:小柯机器人 发布时间:2022/5/26 23:43:30

近日,美国斯坦福大学Jesse M. Engreitz及其团队的最新研究揭示人类增强子和启动子序列的相容性规则。相关论文于2022年5月20日在线发表在《自然》杂志上。

研究人员设计了一种名为ExP STARR-seq(增强子x启动子自转录活性调节区测序)的高通量报告试验,并应用它来研究人类K562细胞中1000个增强子和1000个启动子序列的组合相容性。研究人员确定了增强子-启动子兼容性的简单规则:大多数增强子以类似的数量激活所有启动子,内在的增强子和启动子的活动以倍数结合来决定RNA输出(R2=0.82)。
 
此外,有两类增强子和启动子显示出微妙的偏好效应。管家基因的启动子含有GABPA和YY1等因子的内置激活模体,这降低了启动子对远端增强子的反应性。表达不一的基因的启动子缺乏这些模体,对增强子表现出更强的反应性。总之,这种对增强子-启动子兼容性的系统评估表明,在人类基因组中,有一个由增强子和启动子类型调整的乘法模型来控制基因转录。
 
据了解,人类基因组中的基因调控是由远端增强子控制的,它能激活附近特定的启动子。这种特异性的一个模型是,启动子可能对某些增强子有序列编码的偏好,例如由相互作用的转录因子组或辅助因子介导。这种"生化兼容性"模型已被个别人类启动子的观察和果蝇的全基因组测量所支持。然而,人类增强子和启动子内在兼容的程度还没有得到系统的测量,它们的活动如何结合起来控制RNA的表达仍不清楚。
 
附:英文原文
 
Title: Compatibility rules of human enhancer and promoter sequences

Author: Bergman, Drew T., Jones, Thouis R., Liu, Vincent, Ray, Judhajeet, Jagoda, Evelyn, Siraj, Layla, Kang, Helen Y., Nasser, Joseph, Kane, Michael, Rios, Antonio, Nguyen, Tung H., Grossman, Sharon R., Fulco, Charles P., Lander, Eric S., Engreitz, Jesse M.

Issue&Volume: 2022-05-20

Abstract: Gene regulation in the human genome is controlled by distal enhancers that activate specific nearby promoters1. One model for this specificity is that promoters might have sequence-encoded preferences for certain enhancers, for example mediated by interacting sets of transcription factors or cofactors2. This “biochemical compatibility” model has been supported by observations at individual human promoters and by genome-wide measurements in Drosophila3–9. However, the degree to which human enhancers and promoters are intrinsically compatible has not been systematically measured, and how their activities combine to control RNA expression remains unclear. Here we designed a high-throughput reporter assay called ExP STARR-seq (enhancer x promoter self-transcribing active regulatory region sequencing) and applied it to examine the combinatorial compatibilities of 1,000 enhancer and 1,000 promoter sequences in human K562 cells. We identify simple rules for enhancer-promoter compatibility: most enhancers activated all promoters by similar amounts, and intrinsic enhancer and promoter activities combine multiplicatively to determine RNA output (R2=0.82). In addition, two classes of enhancers and promoters showed subtle preferential effects. Promoters of housekeeping genes contained built-in activating motifs for factors such as GABPA and YY1, which decreased the responsiveness of promoters to distal enhancers. Promoters of variably expressed genes lacked these motifs and showed stronger responsiveness to enhancers. Together, this systematic assessment of enhancer-promoter compatibility suggests a multiplicative model tuned by enhancer and promoter class to control gene transcription in the human genome.

DOI: 10.1038/s41586-022-04877-w

Source: https://www.nature.com/articles/s41586-022-04877-w

期刊信息

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