Compatibility rules of human enhancer and promoter sequences.
Compatibility rules of human enhancer and promoter sequences.
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人类增强子和启动子序列的相容规则。
DOI：
10.1038/s41586-022-04877-w
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发表时间：
2022-07
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
人类基因组中的基因调控由激活附近特定启动子的远端增强子控制。这种特异性的一个模型是启动子可能对某些增强子具有序列编码的偏好，例如通过一组相互作用的转录因子或辅因子介导。这种“生化相容性”模型得到了对个体人类启动子的观察和果蝇全基因组测量的支持。然而，人类增强子和启动子本质上相容的程度尚未得到系统测量，并且它们的活性如何结合来控制 RNA 表达仍不清楚。在这里，我们设计了一种名为 ExP STARR-seq（增强子 x 启动子自转录活性调节区测序）的高通量报告基因检测，并将其应用于检查人 K562 细胞中 1,000 个增强子和 1,000 个启动子序列的组合兼容性。我们确定了增强子-启动子兼容性的简单规则：大多数增强子以相似的量激活所有启动子，并且内在增强子和启动子活性相乘地组合以确定RNA输出（R2=0.82）。此外，两类增强子和启动子表现出微妙的优先效应。持家基因的启动子含有 GABPA 和 YY1 等因子的内置激活基序，这降低了启动子对远端增强子的反应性。可变表达基因的启动子缺乏这些基序，并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，通过增强子和启动子类别调整乘法模型来控制人类基因组中的基因转录。
Gene regulation in the human genome is controlled by distal enhancers that activate specific nearby promoters. 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 cofactors. This “biochemical compatibility” model has been supported by observations at individual human promoters and by genome-wide measurements in Drosophila. 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.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
64.8
作者：
Harris CR;Millman KJ;van der Walt SJ;Gommers R;Virtanen P;Cournapeau D;Wieser E;Taylor J;Berg S;Smith NJ;Kern R;Picus M;Hoyer S;van Kerkwijk MH;Brett M;Haldane A;Del Río JF;Wiebe M;Peterson P;Gérard-Marchant P;Sheppard K;Reddy T;Weckesser W;Abbasi H;Gohlke C;Oliphant TE
通讯作者：
Oliphant TE
影响因子：
10.5
作者：
Butler, JEF;Kadonaga, JT
通讯作者：
Kadonaga, JT
影响因子：
30.8
作者：
Fulco, Charles P.;Nasser, Joseph;Engreitz, Jesse M.
通讯作者：
Engreitz, Jesse M.
影响因子：
10.5
作者：
Emami, KH;Jain, A;Smale, ST
通讯作者：
Smale, ST