Multi-Scale Dynamical Modelling of T-Cell Development from an Early Thymic Progenitor State to Lineage Commitment

Abstract

Intrathymic 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, proliferation, and ultimately commitment. To explain these features in light of recently measured epigenetic effects and new experimental data, we developed a three-level dynamic model of commitment based upon regulation of the commitment-linked gene Bcl11b. The levels are: (1) a core gene regulatory network architecture determined by transcription factor (TF) perturbation data, (2) a stochastically controlled epigenetic gate, and (3) a single-cell proliferation model validated by experimental clonal growth and commitment kinetic assays. Using values from RNA-FISH measurements of genes encoding key TFs and bulk population dynamics, this single-cell model predicts state switching kinetics validated by measured clonal proliferation and commitment times. The resulting multi-scale model provides a novel approach and mechanistic framework for dissecting commitment dynamics.