GRaNIE and GRaNPA: inference and evaluation of enhancer-mediated gene regulatory networks.

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Molecular Systems Biology Pub Date : 2023-06-12 Epub Date: 2023-04-19 DOI:10.15252/msb.202311627
Aryan Kamal, Christian Arnold, Annique Claringbould, Rim Moussa, Nila H Servaas, Maksim Kholmatov, Neha Daga, Daria Nogina, Sophia Mueller-Dott, Armando Reyes-Palomares, Giovanni Palla, Olga Sigalova, Daria Bunina, Caroline Pabst, Judith B Zaugg
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引用次数: 18

Abstract

Enhancers play a vital role in gene regulation and are critical in mediating the impact of noncoding genetic variants associated with complex traits. Enhancer activity is a cell-type-specific process regulated by transcription factors (TFs), epigenetic mechanisms and genetic variants. Despite the strong mechanistic link between TFs and enhancers, we currently lack a framework for jointly analysing them in cell-type-specific gene regulatory networks (GRN). Equally important, we lack an unbiased way of assessing the biological significance of inferred GRNs since no complete ground truth exists. To address these gaps, we present GRaNIE (Gene Regulatory Network Inference including Enhancers) and GRaNPA (Gene Regulatory Network Performance Analysis). GRaNIE (https://git.embl.de/grp-zaugg/GRaNIE) builds enhancer-mediated GRNs based on covariation of chromatin accessibility and RNA-seq across samples (e.g. individuals), while GRaNPA (https://git.embl.de/grp-zaugg/GRaNPA) assesses the performance of GRNs for predicting cell-type-specific differential expression. We demonstrate their power by investigating gene regulatory mechanisms underlying the response of macrophages to infection, cancer and common genetic traits including autoimmune diseases. Finally, our methods identify the TF PURA as a putative regulator of pro-inflammatory macrophage polarisation.

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GRaNIE和GRaNPA:增强子介导的基因调控网络的推断和评估。
增强子在基因调控中起着至关重要的作用,在介导与复杂性状相关的非编码遗传变异的影响方面至关重要。增强子活性是一种受转录因子(TF)、表观遗传学机制和遗传变异调控的细胞类型特异性过程。尽管转录因子和增强子之间有很强的机制联系,但我们目前缺乏在细胞类型特异性基因调控网络(GRN)中联合分析它们的框架。同样重要的是,我们缺乏一种公正的方法来评估推断的GRN的生物学意义,因为不存在完整的基本事实。为了解决这些差距,我们提出了GRaNIE(包括增强子的基因调控网络推断)和GRaNPA(基因调控网络性能分析)。GRaNIE(https://git.embl.de/grp-zaugg/GRaNIE)基于染色质可及性和样本(如个体)RNA-seq的协变构建增强子介导的GRN,而GRaNPA(https://git.embl.de/grp-zaugg/GRaNPA)评估GRN预测细胞类型特异性差异表达的性能。我们通过研究巨噬细胞对感染、癌症和包括自身免疫性疾病在内的常见遗传特征的反应的基因调节机制来证明它们的力量。最后,我们的方法确定TF PURA是促炎巨噬细胞极化的假定调节因子。
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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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