Swimming Upstream: Identifying Proteomic Signals that Drive Transcriptional Changes using the Interactome and Multiple " -Omics" Datasets

Shao shan Carol Huang, Ernest Fraenkel

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Signaling and transcription are tightly integrated processes that underlie many cellular responses to the environment. A network of signaling events, often mediated by post-translational modification on proteins, can lead to long-term changes in cellular behavior by altering the activity of specific transcriptional regulators and consequently the expression level of their downstream targets. As many high-throughput, " -omics" methods are now available that can simultaneously measure changes in hundreds of proteins and thousands of transcripts, it should be possible to systematically reconstruct cellular responses to perturbations in order to discover previously unrecognized signaling pathways.This chapter describes a computational method for discovering such pathways that aims to compensate for the varying levels of noise present in these diverse data sources. Based on the concept of constraint optimization on networks, the method seeks to achieve two conflicting aims: (1) to link together many of the signaling proteins and differentially expressed transcripts identified in the experiments " . constraints" using previously reported protein-protein and protein-DNA interactions, while (2) keeping the resulting network small and ensuring it is composed of the highest confidence interactions " . optimization" . A further distinctive feature of this approach is the use of transcriptional data as evidence of upstream signaling events that drive changes in gene expression, rather than as proxies for downstream changes in the levels of the encoded proteins.We recently demonstrated that by applying this method to phosphoproteomic and transcriptional data from the pheromone response in yeast, we were able to recover functionally coherent pathways and to reveal many components of the cellular response that are not readily apparent in the original data. Here, we provide a more detailed description of the method, explore the robustness of the solution to the noise level of input data and discuss the effect of parameter values.

Original languageEnglish (US)
Title of host publicationMethods in Cell Biology
PublisherAcademic Press Inc.
Pages57-80
Number of pages24
DOIs
StatePublished - 2012

Publication series

NameMethods in Cell Biology
Volume110
ISSN (Print)0091-679X

Keywords

  • Acetylation
  • Interactome
  • Mass spectrometry
  • Phosphorylation
  • Reliability
  • Transcription factor

ASJC Scopus subject areas

  • Cell Biology

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    Huang, S. S. C., & Fraenkel, E. (2012). Swimming Upstream: Identifying Proteomic Signals that Drive Transcriptional Changes using the Interactome and Multiple " -Omics" Datasets. In Methods in Cell Biology (pp. 57-80). (Methods in Cell Biology; Vol. 110). Academic Press Inc.. https://doi.org/10.1016/B978-0-12-388403-9.00003-5