MC EMiNEM Maps the Interaction Landscape of the Mediator

Theresa Niederberger,Achim Tresch,Dietmar E Martin,Stefanie Etzold,Michael Lidschreiber,Kerstin C Maier,Patrick Cramer,Holger Fröhlich,Adam Siepel

doi:10.1371/journal.pcbi.1002568

Abstract

The Mediator is a highly conserved, large multiprotein complex that is involved essentially in the regulation of eukaryotic mRNA transcription. It acts as a general transcription factor by integrating regulatory signals from gene-specific activators or repressors to the RNA Polymerase II. The internal network of interactions between Mediator subunits that conveys these signals is largely unknown. Here, we introduce MC EMiNEM, a novel method for the retrieval of functional dependencies between proteins that have pleiotropic effects on mRNA transcription. MC EMiNEM is based on Nested Effects Models (NEMs), a class of probabilistic graphical models that extends the idea of hierarchical clustering. It combines mode-hopping Monte Carlo (MC) sampling with an Expectation-Maximization (EM) algorithm for NEMs to increase sensitivity compared to existing methods. A meta-analysis of four Mediator perturbation studies in Saccharomyces cerevisiae, three of which are unpublished, provides new insight into the Mediator signaling network. In addition to the known modular organization of the Mediator subunits, MC EMiNEM reveals a hierarchical ordering of its internal information flow, which is putatively transmitted through structural changes within the complex. We identify the N-terminus of Med7 as a peripheral entity, entailing only local structural changes upon perturbation, while the C-terminus of Med7 and Med19 appear to play a central role. MC EMiNEM associates Mediator subunits to most directly affected genes, which, in conjunction with gene set enrichment analysis, allows us to construct an interaction map of Mediator subunits and transcription factors.

Highlights

The Mediator, first discovered by Kim et al (1994) and Koleske et al (1994) [1,2], is a large multiprotein complex which is highly conserved in eukaryotes [3]
Nested Effects Models Nested Effects Models (NEMs) are probabilistic graphical models designed for the analysis of gene expression data from perturbation experiments
NEMs split this flow into two parts: the signals graph H containing the edges between the perturbed entities, and the effects graph H describing the assignment of the effect nodes to the signal nodes

Summary

Introduction

The Mediator, first discovered by Kim et al (1994) and Koleske et al (1994) [1,2], is a large multiprotein complex which is highly conserved in eukaryotes [3]. Yeast Mediator consists of 25 subunits, organized in 4 different modules: head, middle, tail, and kinase module. It is a general transcription factor (TF) that acts as an interface between gene-specific transcription factors and the core transcription machinery (e.g., Polymerase II). Though being a well-studied complex, the Mediator still raises a number of unanswered questions: How do the individual subunits contribute to the Mediator’s functions? How is the regulatory information transferred within the Mediator complex, and how does it convey these signals to the core transcription machinery? Though being a well-studied complex, the Mediator still raises a number of unanswered questions: How do the individual subunits contribute to the Mediator’s functions? How is the regulatory information transferred within the Mediator complex, and how does it convey these signals to the core transcription machinery?

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Methods

Conclusion