Predicting transcription factor activity using prior biological information

Abstract

Transcription factors are critical regulators of cellular gene expression programs. Disruption of normal transcription factor regulation is associated with a broad range of diseases. In order to understand the mechanisms that underly disease pathogenesis, it is critical to detect aberrant transcription factor activity. We have developed Priori, a computational method to predict transcription factor activity from RNA sequencing data. Priori has several key advantages over existing methods. Priori utilizes literature-supported regulatory relationship information to identify known transcription factor target genes. Using these transcriptional relationships, Priori uses linear models to determine the impact and direction of transcription factor regulation on the expression of its target genes. In our work, we evaluated the ability of Priori and 16 other methods to detect aberrant activity from 124 single-gene perturbation experiments. We show that Priori identifies perturbed transcription factors with greater sensitivity and specificity than other methods. Furthermore, our work demonstrates that Priori can be used to discover significant determinants of survival in breast cancer as well as identify mediators of drug response in leukemia from primary patient samples.