Metadomain and metaloop genome interactions in mammalian T cells

Dolsten, G.; Wang, Z.-M.; Huang, X.; Song, S.; Wilson, M. J.; Bing, X. Y.; Ke, W.; Cafiero, T. R.; Nelson, A. N.; Fernando, S.; Ploss, A.; Schedl, P.; Levine, M. S.; Viny, A. D.; Rudensky, A. Y.; Pritykin, Y.

doi:10.1101/2025.09.19.677419

bioRxiv · 10.1101/2025.09.19.677419

Metadomain and metaloop genome interactions in mammalian T cells

Dolsten, G.·Wang, Z.-M.·Huang, X.·Song, S.·Wilson, M. J.·Bing, X. Y.·Ke, W.·Cafiero, T. R.·Nelson, A. N.·Fernando, S.·Ploss, A.·Schedl, P.·Levine, M. S.·Viny, A. D.·Rudensky, A. Y.·Pritykin, Y.

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Abstract

Recent studies have advanced our understanding of chromosomal organization and its principal role in gene regulation. However, most analyses have focused on short-range interactions (<2 Mb), limiting insight into broader regulatory architecture. In particular, the relationships between topologically associating domains (TADs), sub-TAD loops, long-range cross-TAD interactions, and higher-order chromosomal compartmentalization remain poorly understood. Here, we identify extensive multi-megabase and interchromosomal interactions (metaloops) in T lymphocytes, which organize into larger meta-TAD associations (metadomains). Metaloops bridge distal promoters and regulatory elements of key T cell-specific genes such as Ctla4, Ikzf2, Il2ra, Ets1, Lef1, Runx1, Bach2, Foxo1 and others, and are both shared and cell type-specific across functionally distinct T cell lineages. Reanalysis of published data confirms the reproducibility of these interactions in both mouse and human T cells and their dependence on superenhancers. Genome-wide clustering of metadomains reveals three interchromosomal hubs with distinct epigenomic profiles, including a superenhancer-enriched hub associated with T cell-specific gene activation. By integrating a compendium of new and public T cell epigenomic data, we infer distinct architectural factors associated with short-range loops and long-range metaloops. Altogether, our study reveals new features of T cell-specific 3D genome organization across scales, and our computational framework is broadly applicable to analyses of chromatin architecture across different cell types and experimental systems. Highlights- Ultra-long-range (>2 Mb) chromatin interactions linked to gene regulation in T cells - A new algorithm identifies distal and interchromosomal meta-TADs and metaloops - An interchromosomal T cell-specific active hub emerges from metadomain clustering - Epigenomic compendium implicates TFs associated with long-range interactions

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Dolsten, G., Wang, Z.-M., Huang, X., Song, S., Wilson, M. J., Bing, X. Y., Ke, W., Cafiero, T. R., Nelson, A. N., Fernando, S., Ploss, A., Schedl, P., Levine, M. S., Viny, A. D., Rudensky, A. Y., Pritykin, Y.. 2025-09-21. Metadomain and metaloop genome interactions in mammalian T cells. https://doi.org/10.1101/2025.09.19.677419

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