Reverse Engineering of Signal Transduction Pathways

Andrea Califano, Columbia University - "Genome-wide Discovery of Post-translational Modulators of Transcriptional Interactions in Human B Lymphocytes"
Martin Steffen, Boston University - "Systems Immunology: Coordinating The Response Of Immune Cells In COPD"
Peter Sorger, MIT - "Systems biology of life-death decisions"

Andrea Califano: "Genome-wide Discovery of Post-translational Modulators of Transcriptional Interactions in Human B Lymphocytes"

Transcriptional interactions in the cell are modulated by a variety of mechanisms that prevent their representation as pairwise interactions between a transcription factor and its targets. These include, among others, transcription factor modification by phosphorylation and acetylation, formation of active complexes with one or more transcriptional co-factors, and protein specific degradation and stabilization processes. We introduce a method for the genome-wide computational inference of post-translational modulators of a transcription factor, which are able to affect the ability of the TF to activate/repress its targets. This information theoretic method, MINDY, directly analyzes the multivariate statistical dependencies between a transcription factor and one or more of its targets, conditional on the presence (or absence) of a candidate modulator gene. MINDY has been validated extensively in a mammalian cellular network context by identifying post-translational modulators of both the MYC and BCL6 proto-oncogenes, from a set of 254 microarray expression profiles of normal and tumor related human B lymphocytes. Discovered modulators are highly enriched in signaling proteins and transcription factors, recapitulate established regulation pathways and known interaction partners, and provides a new repertoire of post-transcriptional modulators of these two genes. Results have been biochemically validated showing that new protein-protein interaction can be effectively identified by this method. Finally, we extend the method to the genome-wide analysis of all co-TF, kinases, and phosphatases capable of modulating any TFs that have sufficient expression range in human B cells. This provides a novel repertoire of candidate drug-targets that are able to repress or activate specific transcriptional programs.

Martin Steffen: "Systems Immunology: Coordinating The Response Of Immune Cells In COPD"

The cells of the immune system work together as a unit to protect individuals against infection and to eradicate disease, with neutrophils and monocytes playing roles in innate immunity, and T-helper lymphocytes coordinating the humoral (B-cell) and cellular (cytolytic T-cell) adaptive immune responses. The coordination of events among these multiple cell types is achieved by the secretion of cytokines which bind to receptors and trigger signal transduction cascades. This talk will describe our efforts to understand the coordinated activity of various immune cell types in a disease characterized by abnormal inflammation. Chronic Obstructive Pulmonary Disease, or COPD, includes emphysema and chronic bronchitis, and is characterized by a progressive airflow limitation. We will discuss computational modeling of protein interaction networks, mass spectrometric identification of protein expression levels, and genetic association studies, which together suggest an altered role for the multi-subunit proteasome complex in inflammation in affected individuals.

Peter Sorger: "Systems biology of life-death decisions"

Cytokines, growth factors and their receptors activate complex signaling cascades that regulate cell proliferation, death and differentiation. We are using a systems biology approach to study cytokine signaling in human cells with an eye towards understanding cell-type variatio