Multi-scale dynamical modelling of T-cell development from an early thymic progenitor state to lineage commitment

Abstract

Thymic development of committed pro-T-cells from multipotent hematopoietic precursors offers a unique opportunity to dissect the molecular circuitry establishing cell identity in response to environmental signals. This transition encompasses programmed shutoff of stem/progenitor genes, upregulation of T-cell specification genes, extensive proliferation, and commitment after a delay. We have incorporated these factors, as well as new single cell gene expression and developmental kinetics data, into a three-level dynamic model of commitment based upon regulation of the commitment gene Bcl11b. The first level is a core gene regulatory network architecture determined by transcription factor perturbation data, the second a stochastically controlled epigenetic gate, and the third a proliferation model validated by growth and commitment kinetics measured at single-cell levels. Using expression values consistent with single molecule RNA-FISH measurements of key transcription factors, this single-cell model exhibits state switching consistent with measured population and clonal proliferation and commitment times. The resulting multi-scale model provides a powerful mechanistic framework for dissecting commitment dynamics.