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

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 ( aNIE) builds enhancer-mediated GRNs based on covariation of chromatin accessibility and RNA-seq across samples (e.g. individuals), while 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.

Automated summary

Enhancers are crucial for gene regulation and linked to noncoding genetic variants associated with complex traits. We lack a framework for jointly analyzing transcription factors and enhancers in cell-type-specific gene regulatory networks (GRN) and an unbiased way to evaluate the biological significance of inferred GRNs. To address these gaps, we introduce GRaNIE (Gene Regulatory Network Inference including Enhancers) and GRaNPA (Gene Regulatory Network Performance Analysis). Our methods are demonstrated by studying gene regulatory mechanisms in macrophage response to infection, cancer, and common genetic traits. Furthermore, we identify the TF PURA as a potential regulator of pro-inflammatory macrophage polarization.