Single-cell multiomics identifies Tcf1 and Lef1 as key initiators of early thymic progenitor fate
Recommended Citation
Zhao X, Hu SS, Lee WH, Zakrzewski JL, Mi QS, Rosenstein RK, Zang C, Ma X, and Xue HH. Single-cell multiomics identifies Tcf1 and Lef1 as key initiators of early thymic progenitor fate. Sci Immunol 2025;10(111):eadq8970.
Document Type
Article
Publication Date
9-12-2025
Publication Title
Sci Immunol
Abstract
Bone marrow-derived multipotent hematopoietic progenitors seed the thymus and generate early thymic progenitors (ETPs). However, the factors governing ETP formation remain poorly defined. Using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), we dissected the heterogeneity of transcriptomic and chromatin accessibility landscapes in murine ETPs. Whereas Tcf1(-) ETPs exhibited higher proliferative capacity, Tcf1(+) ETPs appeared to be immediate, more robust precursors to T lineage-specified early thymocytes. Prethymic ablation of Tcf1 and its homolog Lef1 severely impaired ETP formation in vivo. Whereas ablating Tcf1 alone had limited impact, loss of both Tcf1 and Lef1 impaired transcriptional activation of Notch1 and Notch pathway effector molecules, including Hes1 and Hhex, accompanied by aberrantly induced B cell and myeloid gene programs. Acute deletion of both factors compromised Notch pathway, glycolysis, and T cell gene programs in emergent ETPs ex vivo. Thus, Tcf1 and Lef1 act upstream of the Notch pathway, functioning as prethymic initiators of ETP fate and intrathymic gatekeepers of ETP identity and T lineage potential.
Medical Subject Headings
Animals; Lymphoid Enhancer-Binding Factor 1; Mice; Hepatocyte Nuclear Factor 1-alpha; Single-Cell Analysis; Thymus Gland; Cell Differentiation; Mice, Inbred C57BL; Mice, Knockout; Cell Lineage; Thymocytes; Multiomics
PubMed ID
40938954
Volume
10
Issue
111
First Page
8970
Last Page
8970
