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PreprintCC BY-NCbioRxiv

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

  • I. Patrascan
  • J. W. King
  • N. Maziak
  • R. M. Crossley
  • S. Johnson
  • A. Ceccarelli
  • I. McFarlane
  • Y. Guo
  • M. M. Karimi
  • A. G. Fisher
  • R. E. Baker
  • J. M. Vaquerizas
1 more authors
  • M. Merkenschlager1
  1. 1MRC Laboratory of Medical Sciences, Imperial College London
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Abstract

Decades of investigation have made the choice between CD4 and CD8 T cell lineages in the thymus a key paradigm for mammalian cell commitment and differentiation, yet how transcriptional diversification is coordinated with 3D genome organisation remains largely unexplored. Here, using single-molecule transcript quantification and region capture Pico-C (RCPC), we resolve distinct transcriptional and spatial chromatin dynamics at the lineage-defining loci Cd4 and Cd8. We find early Cd4/Cd8 transcriptional divergence driven by MHC-dependent bias in Cd8a transcript copy number, which unfolds gradually across both CCR7- and CCR7+ differentiation stages. Unexpectedly, Cd4 and Cd8 loci show fundamentally different spatial contact dynamics: transiently reduced mesoscale (10-100kb) contacts at Cd8 provide a permissive chromatin environment throughout the transcriptional diversification process. By contrast, Cd4 undergoes switch-like contact changes limited to the microscale (1kb) late in differentiation, associated with lineage stabilization by ThPOK and/or RUNX3. These results place distinct, locus-specific chromatin environments at the centre of transcriptional diversification during T cell lineage choice.

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Cite

BibTeXRIS
BibTeX
@misc{patrascan2026locusspecific,
  title = {{Locus-specific spatial and transcriptional dynamics direct T cell lineage choice in the thymus}},
  author = {I. Patrascan and J. W. King and N. Maziak and R. M. Crossley and S. Johnson and A. Ceccarelli and I. McFarlane and Y. Guo and M. M. Karimi and A. G. Fisher and R. E. Baker and J. M. Vaquerizas and M. Merkenschlager},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.26.761611},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761611v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - Locus-specific spatial and transcriptional dynamics direct T cell lineage choice in the thymus
AU  - I. Patrascan
AU  - J. W. King
AU  - N. Maziak
AU  - R. M. Crossley
AU  - S. Johnson
AU  - A. Ceccarelli
AU  - I. McFarlane
AU  - Y. Guo
AU  - M. M. Karimi
AU  - A. G. Fisher
AU  - R. E. Baker
AU  - J. M. Vaquerizas
AU  - M. Merkenschlager
PY  - 2026
DA  - 2026/10/26
PB  - bioRxiv
DO  - 10.64898/2026.10.26.761611
UR  - https://www.biorxiv.org/content/10.64898/2026.10.26.761611v1
AB  - Decades of investigation have made the choice between CD4 and CD8 T cell lineages in the thymus a key paradigm for mammalian cell commitment and differentiation, yet how transcriptional diversification is coordinated with 3D genome organisation remains largely unexplored. Here, using single-molecule transcript quantification and region capture Pico-C (RCPC), we resolve distinct transcriptional and spatial chromatin dynamics at the lineage-defining loci Cd4 and Cd8. We find early Cd4/Cd8 transcriptional divergence driven by MHC-dependent bias in Cd8a transcript copy number, which unfolds gradually across both CCR7- and CCR7+ differentiation stages. Unexpectedly, Cd4 and Cd8 loci show fundamentally different spatial contact dynamics: transiently reduced mesoscale (10-100kb) contacts at Cd8 provide a permissive chromatin environment throughout the transcriptional diversification process. By contrast, Cd4 undergoes switch-like contact changes limited to the microscale (1kb) late in differentiation, associated with lineage stabilization by ThPOK and/or RUNX3. These results place distinct, locus-specific chromatin environments at the centre of transcriptional diversification during T cell lineage choice.
ER  -