An Integrated Regulatory Network Reveals Pervasive Cross-Regulation among Transcription and Splicing Factors

Idit Kosti,Yael Mandel-Gutfreund,Predrag Radivojac,Sarah A Teichmann

doi:10.1371/journal.pcbi.1002603

Abstract

Traditionally the gene expression pathway has been regarded as being comprised of independent steps, from RNA transcription to protein translation. To date there is increasing evidence of coupling between the different processes of the pathway, specifically between transcription and splicing. To study the interplay between these processes we derived a transcription-splicing integrated network. The nodes of the network included experimentally verified human proteins belonging to three groups of regulators: transcription factors, splicing factors and kinases. The nodes were wired by instances of predicted transcriptional and alternative splicing regulation. Analysis of the network indicated a pervasive cross-regulation among the nodes; specifically, splicing factors are significantly more connected by alternative splicing regulatory edges relative to the two other subgroups, while transcription factors are more extensively controlled by transcriptional regulation. Furthermore, we found that splicing factors are the most regulated of the three regulatory groups and are subject to extensive combinatorial control by alternative splicing and transcriptional regulation. Consistent with the network results, our bioinformatics analyses showed that the subgroup of kinases have the highest density of predicted phosphorylation sites. Overall, our systematic study reveals that an organizing principle in the logic of integrated networks favor the regulation of regulatory proteins by the specific regulation they conduct. Based on these results, we propose a new regulatory paradigm postulating that gene expression regulation of the master regulators in the cell is predominantly achieved by cross-regulation.

Highlights

The operation of a functioning living cell depends on its ability to tightly regulate its different pathways
Alternative splicing is regulated by splicing factors that bind to short regulatory motifs on the RNA and dictate the final gene architecture
Analysis of the network indicated that splicing factors were more often regulated by alternative splicing while transcription factors were more extensively controlled by transcriptional regulation

Summary

Introduction

The operation of a functioning living cell depends on its ability to tightly regulate its different pathways. The physical coupling between the different steps is known to be mediated by the CTD (C-Terminal Domain) of the largest subunit of RNA polymerase II that is recruited to the transcription complex by specific TFs [7]. This coupling is required both for efficient gene expression in higher eukaryotes and for enabling rapid response to diverse signaling events in the cell [8]. It was shown that an AS event within a TF mRNA encoding a DNA-binding protein alters the transcription regulatory network controlling the transition between pluripotency and differentiation in embryonic stem cells [10]. Since AS can remove or insert short fragments in a protein, it may alter the phosphorylation pattern of the protein,

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