Automated Identification of Core Regulatory Genes in Human Gene Regulatory Networks

Vipin Narang, Muhamad Azfar Ramli, Amit Singhal, Pavanish Kumar, Gennaro de Libero, Michael Poidinger, Christopher P. Monterola

Abstract: Author Summary A gene regulatory network (GRN) represents how some genes encoding regulatory molecules such as transcription factors or microRNAs regulate the expression of other genes. Researchers commonly study GRNs involved in a specific biological process with the aim of identifying a few important regulatory genes. In higher organisms such as humans, a regulatory gene regulates multiple target genes and correspondingly any gene is regulated by multiple regulatory genes. Due to such multiplicity of interactions, a GRN usually resembles a tangled hairball wherein it is difficult to identify few most influential regulatory genes. In this study, we show that network analysis algorithms such as K-core, pagerank and betweenness centrality are useful for identifying a few important or core regulatory genes in a GRN, and the K-core algorithm is also useful for organizing regulatory genes in a hierarchical layered structure where the most influential genes in a GRN are found within the innermost layer or core. These few core regulatory genes determine to a large extent the expression status of the remaining genes in the network. We illustrate a pragmatic application of this technique to GRNs reconstructed from genome-wide gene expression measurements in the MCF-7 human breast cancer cell line.