The Rothenberg group studies the molecular mechanisms that are responsible for developmental lineage choice as hematopoietic stem cells differentiate into T lymphocytes. This is a complex process in which stem-cell multipotentiality is lost in steps that actually overlap with the initiation of T-cell specific differentiation events. Thus, it offers unique insights into the nature of "stem-ness" and the distinction between activation of a development program and irreversible commitment to that program. The approaches used in the lab are a combination of in vitro developmental biology, high-resolution characterization of individual cell developmental states, and molecular genetics of gene regulation. We focus on identifying the transcription factors and signaling events that induce T-lineage gene expression in an uncommitted precursor and determine also how they work to force the cell to relinquish other developmental options. Kinetic dissection of this complex process using in vitro differentiation systems and retroviral perturbation make it possible to solve the roles of individual regulatory molecules in successive, highly-defined developmental contexts. This system also turns out to be extremely illuminating about the power of transcription factor-transcription factor interactions in stem-cell based developmental systems more broadly. Mechanistic insight comes from genome-wide analyses of how transcription factors interact with the changing chromatin landscapes at distinct stages in the lineage commitment process, in order to account for the distinctive kinetics and eventual irreversibility of this developmental process. In addition, our group is interested in the subtle variations in this pathway that may predispose to autoimmunity, and the evolutionary origins of the T, B, and innate lymphocyte developmental programs by comparative analysis of basal vertebrates.