Aging-associated SATB1 deficiency remodels 3D genome architecture and transcriptional programs in naive CD4⁺ T cells

Precise three-dimensional (3D) genome organization is crucial for regulating gene expression during development, yet its role in age-related transcriptional changes and physiological decline remains elusive. Here, we show that aging reshapes chromatin architecture and gene regulation in murine naive CD4⁺ T cells, a quiescent T cell population essential for adaptive immunity. Aged naive CD4⁺ T cells exhibit intrinsic transcriptional reprogramming marked by increased expression of inflammatory and T cell activation-related genes, rendering them more prone to activation. Intriguingly, these changes are accompanied by pronounced alterations in 3D genome organization, including widespread weakening of TAD boundaries and extensive enhancer-promoter rewiring. Mechanistically, we demonstrate that these age-associated structural changes can be partly attributed to the diminished expression of chromatin organizer SATB1. SATB1 colocalizes with CTCF in young naive T cells to spatially constrain CTCF binding sites. Its decline with age extends the range of CTCF-mediated interactions without altering CTCF occupancy, leading to remodeling of chromatin architecture and upregulation of pro-inflammatory and pro-activation genes. Conditional SATB1 deletion in naive T cells recapitulates the 3D genome and transcriptional changes observed in aging. Our findings reveal a critical role for SATB1 in maintaining 3D genome integrity in naive T cells, and suggest that the dysregulation of genome architecture contributes to immune and organismal aging.