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

• DOI: 10.1016/j.celrep.2020.108622
• Publication Date: 2021-01-14T06:08:37Z
• Authors: Victor Olariu; Mary A. Yui; Pawel Krupinski; Wen Zhou; Julia Deichmann; Emil Andersson; Ellen V. Rothenberg; Carsten Peterson
• Keywords: 0301 basic medicine; 570; 0303 health sciences; QH301-705.5; single-cell measurements; Stem Cells; T-Lymphocytes; T cell development; epigenetic modeling; 610; stochastic simulations; Cell Differentiation; Thymus Gland; proliferation measurements; 03 medical and health sciences; transcriptional modeling; Humans; Cell Lineage; experimental validations; kinetic measurements; Biology (General); population modeling

AbstractThymic 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 geneBcl11b. 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.