From components to circuits: reconstructing dynamic regulatory networks in the immune system.
Dr. Nir Yosef - Harvard/MIT Broad Institute
Monday, January 28, 2013, 10:00-11:00 am 
Abstract
Complex, interacting systems are omnipresent in the world, from our social networks to the molecular circuits that guide
the behavior of our cells. Charting out and extracting useful information from such systems has proven an
extremely important, yet often daunting task. In this talk I will describe my work on modeling molecular circuits that
control complex temporal processes in mammalian cells and explain how we used the resulting models to gain insight into
biological organizational principles and to highlight novel key factors that affect autoimmunity.
Our modeling strategy relies on integration of genome-scale data from heterogeneous sources into a combined temporal
model, taking into account both the activity of the components (gene expression changes over time), and their
interactions (protein-protein, protein-DNA). The resulting model is used for designating putative key regulators, whose
perturbations then serve for validating, refining and annotating the inferred interactions. As our model system, we
investigated the differentiation of autoimmune-inducing Th17 T helper cells, which, despite enormous clinical importance,
remains poorly understood. Using our modeling strategy we derived and experimentally validated a temporal model of the
regulatory network that controls the differentiation of naïve T cells into Th17. The network consists of two
self-reinforcing and mutually antagonistic modules that either suppress or promote the Th17 phenotype and collectively
achieve appropriate balance between Th17 cells and competing T cell lineages. The network highlights several novel genes that
are critical for the differentiation process and may thus have clinical importance for controlling autoimmunity. As example,
we followed up on one of our novel hits, the kinase Sgk1, which normally regulates sodium homeostasis in the cell by
showing that elevated sodium enhances Th17 differentiation. These findings suggest a molecular mechanism by which a high
salt diet – common in the western world – may predispose to the development of autoimmune disease. Overall, our study
identified and validated 41 regulatory factors that are embedded within a comprehensive temporal network and
highlighted organizational principles and novel drug targets for the differentiation of Th17 cells.
Bio
This talk is organized by Adelaide Findlay