CONTOUR v2

Complex-based analysis of dysregulated cellular processes in cancer

Sriganesh Srihari1, Piyush B. Madhamshettiwar1, Sarah Song1, Chao Liu1, Peter T. Simpson2, Kum Kum Khanna3 and Mark A. Ragan1

1Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia
2The University of Queensland Centre for Clinical Research, Brisbane, QLD 4006, Australia
3QIMR-Berghofer Institute of Medical Research, Brisbane QLD 4006
Australia
Contact: sriganesh [dot] m [dot] s [at] gmail


Workflow for CONTOURv2: Linking changes in expression levels of protein complexes to their regulation by transcription factors.

The pipeline here obtains complexes extracted from protein interaction networks using our earlier published CONTOURv1 (Srihari & Ragan, Bioinformatics 2013, 29(12):1553-61)


Change history

21 July 2014: Accepted to BMC Systems Biology

04 July 2014: Updated website. Uploaded corrections to manuscript

20 Jan 2014: Created this website


Abstract

Background
Differential expression analysis of (individual) genes is often used to study their roles in diseases. However, diseases such as cancer are a result of the combined effect of multiple genes. Gene products such as proteins seldom act in isolation, but instead constitute stable multi-protein complexes performing dedicated functions. Therefore, complexes aggregate the effect of individual genes (proteins) and can be used to gain a better understanding of cancer mechanisms. Here, we observe that complexes show considerable changes in their expression, in turn directed by the concerted action of transcription factors (TFs), across cancer conditions. We seek to gain novel insights into cancer mechanisms through a systematic analysis of complexes and their transcriptional regulation.

Results
We integrated large-scale protein-interaction (PPI) and gene-expression datasets to identify complexes that exhibit significant changes in their expression across different conditions in cancer. We devised a log-linear model to relate these changes to the differential regulation of complexes by TFs. The application of our model on two case studies involving pancreatic and familial breast tumour conditions revealed: (i) complexes in core cellular processes, especially those responsible for maintaining genome stability and cell proliferation (e.g. DNA damage repair and cell cycle) show considerable changes in expression; (ii) these changes include decrease and countering increase for different sets of complexes indicative of compensatory mechanisms coming into play in tumours; and (iii) TFs work in cooperative and counteractive ways to regulate these mechanisms. Such aberrant complexes and their regulating TFs play vital roles in the initiation and progression of cancer.

Conclusions
Complexes in core cellular processes display considerable decreases and countering increases in expression, strongly reflective of compensatory mechanisms in cancer. These changes are directed by the concerted action of cooperative and counteractive TFs. Our study highlights the roles of these complexes and TFs and presents several case studies of compensatory processes, thus providing novel insights into cancer mechanisms.


Supplementary materials

Download here

Cite: Srihari S et al., Complex-based analysis of dysregulated cellular processes in cancer, BMC Systems Biology 2014, to appear [PDF].


Acknowledgements:
Funding: Australian NHMRC grant 1028742 to PTS and MAR.

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