Locus-specific spatial and transcriptional dynamics direct T cell lineage choice in the thymus

Cd8 and Cd4 loci show distinct spatial chromatin contact dynamics during thymic CD4/CD8 lineage choice, with Cd8 displaying permissive 10–100 kb mesoscale reductions and Cd4 late 1 kb switch-like changes.

• Why it matters: The study addresses how transcriptional diversification is coordinated with 3D genome organization during mammalian T cell lineage commitment, a largely unexplored coordination problem.
• What they did: Using single-molecule transcript quantification and region capture Pico-C (RCPC), the authors mapped transcriptional and spatial chromatin dynamics at Cd4 and Cd8 across CCR7− and CCR7+ differentiation stages.
• The result: Early Cd4/Cd8 transcriptional divergence is linked to MHC-dependent bias in Cd8a transcript copy number, while Cd8 mesoscale (10–100 kb) contact reductions persist and Cd4 microscale (1 kb) switch-like changes late in differentiation associate with lineage stabilization by ThPOK and/or RUNX3.