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bioRxiv · 10.1101/2025.10.10.681717

Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation

Faryabi, R. B.·Zhou, Y.·Jay, A.·Burget, N.·Friedrich, T.·Yoon, S.·Alsing, J.·Nir, G.·Grosschedl, R.·Vahedi, G.
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Abstract

Multiple enhancers, often located across vast genomic distances, regulate key genes. However, how chromatin topology organization at individual alleles enables cell-type-restricted multi-enhancer gene regulation remains unclear. Using acute protein degradation and time-course population-average chromatin conformation capture in lymphoma, we found that the B-cell- lineage-determining transcription factor EBF1 preferentially positions multiple enhancers at loci containing sparsely distributed genes essential for B-cell identity and oncogenesis. Our time-resolved sub-diffraction optical chromatin architecture tracing of >100,000 alleles in individual lymphoma cells further revealed diverse topological conformations facilitating multi-enhancer interactions. Mechanistically, we found that positioning of enhancers at allelic topological centers is required for their interactions with target promoters, with EBF1 serving as a barrier to the loop-extruding cohesin on enhancers. These findings, which we demonstrate their generalizability to the T-cell-lineage-determining transcription factor TCF1 in T-cell leukemia, suggest that lineage-determining transcription factors radially position enhancers and promoters to enable multi-enhancer regulation of key oncogenes.

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Faryabi, R. B., Zhou, Y., Jay, A., Burget, N., Friedrich, T., Yoon, S., Alsing, J., Nir, G., Grosschedl, R., Vahedi, G.. 2025-10-12. Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation. https://doi.org/10.1101/2025.10.10.681717

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