Linking Proteomic and Transcriptional Data through the Interactome and Epigenome Reveals a Map of Oncogene-induced Signaling

Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections between them. Here we present an approach for building a network of physical links among these data that can be used to prioritize targets for pharmacological intervention. Our method recovers the critical missing links between proteomic and transcriptional data by relating changes in chromatin accessibility to changes in expression and then uses these links to connect proteomic and transcriptome data. We applied our approach to integrate epigenomic, phosphoproteomic and transcriptome changes induced by the variant III mutation of the epidermal growth factor receptor (EGFRvIII) in a cell line model of glioblastoma multiforme (GBM). To test the relevance of the network, we used small molecules to target highly connected nodes implicated by the network model that were not detected by the experimental data in isolation and we found that a large fraction of these agents alter cell viability. Among these are two compounds, ICG-001, targeting CREB binding protein (CREBBP), and PKF118–310, targeting β-catenin (CTNNB1), which have not been tested previously for effectiveness against GBM. At the level of transcriptional regulation, we used chromatin immunoprecipitation sequencing (ChIP-Seq) to experimentally determine the genome-wide binding locations of p300, a transcriptional co-regulator highly connected in the network. Analysis of p300 target genes suggested its role in tumorigenesis. We propose that this general method, in which experimental measurements are used as constraints for building regulatory networks from the interactome while taking into account noise and missing data, should be applicable to a wide range of high-throughput datasets.National Science Foundation (U.S.) (DB1-0821391)National Institutes of Health (U.S.) (Grant U54-CA112967)National Institutes of Health (U.S.) (Grant R01-GM089903)National Institutes of Health (U.S.) (P30-ES002109

Stakeholder management in IOS projects: lessons from an attempt to implement an electronic patient file

Implementing an inter-organizational system (IOS) requires significant organizational as well as technical changes. These will affect stakeholders (upon whom promoters depend) with varying degrees of power and with varying degrees of interest in the system. Identifying stakeholders and understanding the sources of their attitudes will enable promoters to meet their expectations more fully, and hence encourage acceptance. We examine these issues through a theoretically based study of an attempt to introduce an Electronic Patient File system in The Netherlands. All saw that the system would benefit patients, yet powerful players resisted its implementation, fearing it would affect their interests. This paper develops and tests a model of stakeholder management, showing that those with high interest in the system lacked the power to implement it, while those with low interest had the power to block it. These negative attitudes were shaped by concerns not about the system itself, but about the likely effects on working routines, power, culture and finance. This paper implies that those promoting an IOS (in any sector) should, from the outset of a project, identify their power sources and seek to reconcile stakeholder interests

Cities as world-political actors? The “tax haven-free” cities initiative and the politics of public procurement

In recent years, interest in the world-political role of cities has grown. The use of public procurement for promoting world-political goals has also gathered scholarly attention, as has the tax justice policy agenda. This article contributes to these discussions by demonstrating how global responsibility became part of the city of Helsinki’s policy alignments, which were then turned into several concrete initiatives. In particular, I focus on the contrast between the relative ease with which Helsinki became a “Fair Trade” city on the one hand and the difficulties it faced in its attempts to become a “Fair Tax” city on the other. I argue that that these initiatives illustrate how cities can utilize public procurement to promote world-political goals. I also show how the increasing complexity of the required procurement criteria can make the success contingent on help from “emergent entrepreneurs” of social movements. These developments highlight the contradictory and complex effects of the “economization” and “marketization” of the political sphere. While economization isolates many societal issues from political control, it can also allow for politicizing local and global issues in ways that were unthinkable. Finally, adding to the existing research on the world-political role of cities, I demonstrate that a city does not need to be a metropolis in order to act in world politics.Peer reviewe