A central challenge in genomics is to systematically assemble the functional components of cells and tissues into circuits that explain cellular and organismal processes. Working closely with the Epigenomics Program and the Klarman Cell Observatory, we are developing and implementing broadly-applicable approaches to reconstruct circuits in mammalian cells, including technologies for perturbation of molecular functions, measurement of molecular profiles and interactions, and computational algorithms for iteratively building and analyzing integrative circuit models. Ongoing projects focus on innate immune circuits of dendritic cells and the differentiation pathways of T cells.
Innate immune responses to pathogens
In the first few minutes of an infection, the immune system must detect an incoming virus, bacteria, or other pathogen, and initiate a cascade of responses that eventually eliminates the infectious agent. Cells express many sensors to detect pathogens, and activate complex circuits to regulate this response. We have been studying immune cells' response to lipopolysaccharide (LPS), a Gram-negative bacterial component, analyzing the underlying circuitry at many levels (e.g., transcriptional and chromatin regulation, signaling, RNA life cycle, protein life cycle, single cell heterogeneity). The LPS response has become a model system for developing and implementing new experimental and computational approaches.
Team members: Hacohen, Regev
T cell differentiation
During an immune response, naive helper CD4+ T cells differentiate into different subtypes (e.g., Th1, Th2, Th17) that express different cytokines and effector functions. To understand the pathways that drive differentiation, we have used a diverse set of techniques from single cell genomics to animal models of disease to systematically dissect pathways of T cell differentiation, identifying many new factors driving this response and unraveling regulatory modules.