Time- and lineage-resolved transcriptional profiling uncovers gene expression programs and clonal relationships that underlie human T lineage specification

• DOI: 10.1101/2023.10.06.561277
• Publication Date: 2023-10-10T17:55:22Z
• Authors: Yale S. Michaels; Matthew C. Major; Becca Bonham-Carter; Jingqi Zhang; Tiam Heydari; John M. Edgar; Laura Greenstreet; Roser Vilarrasa-B...; Seungjoon Kim; Elizabeth L. Castle; Aden Forrow; M Iliana Ibanez-Rios; Carla Zimmerman; Yvonne Chung; Tara Stach; Nico Werschler; David JHF Knapp; Roser Vento-Tormo; Geoffrey Schiebinger; Peter W. Zandstra
• Keywords: Lineage (genetic); Gene regulatory network; Cell fate determination

Abstract T cells develop from multi-potent hematopoietic progenitors in the thymus and provide adaptive protection against pathogens cancer. However, emergence of human cell-competent blood progenitors, their subsequent specification to lineage, has been challenging capture real time. Here, we leveraged a pluripotent stem cell differentiation system understand transcriptional dynamics fate restriction events that underlie this critical developmental process. Time-resolved single RNA sequencing revealed cell-cycle exit, downregulation multipotent program, upregulation >90 lineage-associated transcription factors all occur within highly co-ordinated narrow window. Computational gene-regulatory network inference elucidated logic lineage specification, uncovering an important role for YBX1. We mapped hierarchy using transcribed barcoding mathematical trajectory discovered mast myeloid potential bifurcate each other early haematopoiesis, upstream restriction. Collectively, our analyses quantitative, time-resolved model with relevance regenerative medicine immunology.