PT - JOURNAL ARTICLE AU - Aryan Kamal AU - Christian Arnold AU - Annique Claringbould AU - Rim Moussa AU - Nila H. Servaas AU - Maksim Kholmatov AU - Neha Daga AU - Daria Nogina AU - Sophia Mueller-Dott AU - Armando Reyes-Palomares AU - Giovanni Palla AU - Olga Sigalova AU - Daria Bunina AU - Caroline Pabst AU - Judith B. Zaugg TI - GRaNIE and GRaNPA: Inference and evaluation of enhancer-mediated gene regulatory networks applied to study macrophages AID - 10.1101/2021.12.18.473290 DP - 2022 Jan 01 TA - bioRxiv PG - 2021.12.18.473290 4099 - http://biorxiv.org/content/early/2022/08/31/2021.12.18.473290.short 4100 - http://biorxiv.org/content/early/2022/08/31/2021.12.18.473290.full AB - Among the biggest challenges in the post-GWAS (genome-wide association studies) era is the interpretation of disease-associated genetic variants in non-coding genomic regions. Enhancers have emerged as key players in mediating the effect of genetic variants on complex traits and diseases. Their activity is regulated by a combination of transcription factors (TFs), epigenetic changes and genetic variants. Several approaches exist to link enhancers to their target genes, and others that infer TF-gene connections. However, we currently lack a framework that systematically integrates enhancers into TF-gene regulatory networks. Furthermore, we lack an unbiased way of assessing whether inferred regulatory interactions are biologically meaningful. Here we present two methods, implemented as user-friendly R packages: GRaNIE (Gene Regulatory Network Inference including Enhancers) for building enhancer-based gene regulatory networks (eGRNs) and GRaNPA (Gene Regulatory Network Performance Analysis) for evaluating GRNs. GRaNIE jointly infers TF-enhancer, enhancer-gene and TF-gene interactions by integrating open chromatin data such as ATAC-Seq or H3K27ac with RNA-seq across a set of samples (e.g. individuals), and optionally also Hi-C data. GRaNPA is a general framework for evaluating the biological relevance of TF-gene GRNs by assessing their performance for predicting cell-type specific differential expression. We demonstrate the power of our tool-suite by investigating gene regulatory mechanisms in macrophages that underlie their response to infection and cancer, their involvement in common genetic diseases including autoimmune diseases, and identify the TF PURA as putative regulator of pro-inflammatory macrophage polarisation.Availability- GRaNIE: https://bioconductor.org/packages/release/bioc/html/GRaNIE.html- GRaNPA: https://git.embl.de/grp-zaugg/GRaNPACompeting Interest StatementThe authors have declared no competing interest.