Gene-regulatory programs that specify age-related differences during thymocyte development

Divya Ganapathi Sankaran; Hongya Zhu; Viviana I Maymi; Isabel M Forlastro; Ya Jiang; Nathan Laniewski; Kristin M Scheible; Brian D Rudd; Andrew Grimson

doi:10.1016/j.celrep.2025.115903

Gene-regulatory programs that specify age-related differences during thymocyte development

Cell Rep. 2025 Jun 25;44(7):115903. doi: 10.1016/j.celrep.2025.115903. Online ahead of print.

Authors

Divya Ganapathi Sankaran¹, Hongya Zhu¹, Viviana I Maymi², Isabel M Forlastro², Ya Jiang¹, Nathan Laniewski³, Kristin M Scheible³, Brian D Rudd², Andrew Grimson⁴

Affiliations

¹ Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
² Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
³ David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
⁴ Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA. Electronic address: agrimson@cornell.edu.

PMID: 40570375
DOI: 10.1016/j.celrep.2025.115903

Abstract

T cell development is fundamental to immune system establishment, but how this development changes with age remains poorly understood. Here, we construct a transcriptional and chromatin accessibility atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene-regulatory programs and their link to age-related differences. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern the effector response and cell cycle. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing readout, to uncover a conserved transcriptional regulator, Zbtb20, that contributes to age-dependent differences in T cell development. In summary, our study defines gene-regulatory programs that regulate age-specific differences in T cell development.

Keywords: CD8(+) T cell; CP: Immunology; HSCs; RNA-seq; T cell development; adults; double negative; double positive; immune; neonates; single positive.