Journal Article

Quantitative assessment of protein activity in orphan tissues and single cells using the metaVIPER algorithm

Gonzalez, Christian, Canoll, Peter D., Ding, Hongxu, Douglass, Eugene F., Sonabend, Adam M., Alvarez, Mariano J., Bose, Sayantan, Mela, Angeliki, Sims, Peter A., Califano, Andrea

2018

Overview

We and others have shown that transition and maintenance of biological states is controlled by master regulator proteins, which can be inferred by interrogating tissue-specific regulatory models (interactomes) with transcriptional signatures, using the VIPER algorithm. Yet, some tissues may lack molecular profiles necessary for interactome inference (orphan tissues), or, as for single cells isolated from heterogeneous samples, their tissue context may be undetermined. To address this problem, we introduce metaVIPER, an algorithm designed to assess protein activity in tissue-independent fashion by integrative analysis of multiple, non-tissue-matched interactomes. This assumes that transcriptional targets of each protein will be recapitulated by one or more available interactomes. We confirm the algorithm’s value in assessing protein dysregulation induced by somatic mutations, as well as in assessing protein activity in orphan tissues and, most critically, in single cells, thus allowing transformation of noisy and potentially biased RNA-Seq signatures into reproducible protein-activity signatures. VIPER has been successfully used to assess the regulatory activities of proteins from gene expression data, but its dependence on tissue-specific molecular profiles limits its applicability. MetaVIPER, introduced here, enables inference of the protein activities in orphan tissues and single cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 45/91 / 631/114 / 631/553 / Algorithms / Animals / B-Lymphocytes - cytology / B-Lymphocytes - immunology / Brain Neoplasms - genetics / Brain Neoplasms - metabolism / Brain Neoplasms - pathology / Cell Lineage - genetics / Cell Lineage - immunology / Disease Models, Animal / Gene Expression Regulation / Gene Regulatory Networks / Genetic transformation / Glioblastoma - genetics / Glioblastoma - metabolism / Glioblastoma - pathology / Humanities and Social Sciences / Humans / Mice / multidisciplinary / Mutation / Organ Specificity / Protein Interaction Mapping / Proteins / Ribonucleic acid / RNA / Science / Science (multidisciplinary) / Signatures / Single-Cell Analysis - methods / Tissues / Transcription / Transcription Factors - genetics / Transcription Factors - immunology