A reverse-engineering approach to dissect post-translational modulators of transcription factor's activity from transcriptional data.
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.
The Telethon Institute of Genetics and Medicine, Naples, Italy. gennaro.1.gambardella@kcl.ac.uk.|Present Address: Department of Cancer Studies, King's College London, NHH, London, UK. gennaro.1.gambardella@kcl.ac.uk.
Gennaro
G
Gambardella
The Telethon Institute of Genetics and Medicine, Naples, Italy. peluso@tigem.it.
Ivana
I
Peluso
The Telethon Institute of Genetics and Medicine, Naples, Italy. montefusco@tigem.it.
Sandro
S
Montefusco
Columbia Initiative in Systems Biology and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA. mb3113@c2b2.columbia.edu.
Mukesh
M
Bansal
The Telethon Institute of Genetics and Medicine, Naples, Italy. medina@tigem.it.
Diego L
DL
Medina
Department of Computer Science, University of Sheffield, Sheffield, UK. N.Lawrence@dcs.sheffield.ac.uk.
Neil
N
Lawrence
The Telethon Institute of Genetics and Medicine, Naples, Italy. dibernardo@tigem.it.
Diego
D
di Bernardo
D005786:Gene Expression Regulation / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D014157:Transcription Factors