A reverse-engineering approach to dissect post-translational modulators of transcription factor's activity from transcriptional data

Gennaro Gambardella, Ivana Peluso, Sandro Montefusco, Mukesh Bansal, Diego L. Medina, Neil Lawrence, Diego di Bernardo

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Transcription factors (TFs) act downstream of the major signalling pathways functioning as master regulators of cell fate. Their activity is tightly regulated at the transcriptional, post-transcriptional and post-translational level. Proteins modifying TF activity are not easily identified by experimental high-throughput methods. Results: We developed a computational strategy, called Differential Multi-Information (DMI), to infer post-translational modulators of a transcription factor from a compendium of gene expression profiles (GEPs). DMI is built on the hypothesis that the modulator of a TF (i.e. kinase/phosphatases), when expressed in the cell, will cause the TF target genes to be co-expressed. On the contrary, when the modulator is not expressed, the TF will be inactive resulting in a loss of co-regulation across its target genes. DMI detects the occurrence of changes in target gene co-regulation for each candidate modulator, using a measure called Multi-Information. We validated the DMI approach on a compendium of 5,372 GEPs showing its predictive ability in correctly identifying kinases regulating the activity of 14 different transcription factors. Conclusions: DMI can be used in combination with experimental approaches as high-throughput screening to efficiently improve both pathway and target discovery. An on-line web-tool enabling the user to use DMI to identify post-transcriptional modulators of a transcription factor of interest che be found at http://dmi.tigem.it .

Original languageEnglish
Article number279
JournalBMC Bioinformatics
Volume16
Issue number1
DOIs
Publication statusPublished - Sep 3 2015

ASJC Scopus subject areas

  • Applied Mathematics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Computer Science Applications

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