Non-coding RNA controls long-range enhancer-promoter interactions

Sagropoulou, S.; Velychko, T.; Laparra Cuervo, L.; Stitzinger, S.; Nicol, J.; Walshe, J.; Yan, Y.; Ramasamy, S.; tom Dieck, L.; Bahr, F.; Dybkov, O.; Urlaub, H.; Zumer, K.; Lidschreiber, M.; Oudelaar, A. M.

doi:10.64898/2026.11.10.765568

bioRxiv · 10.64898/2026.11.10.765568

Non-coding RNA controls long-range enhancer-promoter interactions

Sagropoulou, S.·Velychko, T.·Laparra Cuervo, L.·Stitzinger, S.·Nicol, J.·Walshe, J.·Yan, Y.·Ramasamy, S.·tom Dieck, L.·Bahr, F.·Dybkov, O.·Urlaub, H.·Zumer, K.·Lidschreiber, M.·Oudelaar, A. M.

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Abstract

Transcription regulation depends on interactions between enhancers and gene promoters, which often occur over large genomic distances. The molecular drivers of long-range enhancer-promoter interactions remain poorly understood. Enhancers themselves are known to be transcribed into non-coding RNAs, but the function of these transcripts is unclear. Here, we use acute genetic and chemical perturbations of transcription elongation and termination to study the role of non-coding RNA in enhancer-promoter interactions. By integrating high-resolution 3D genome mapping, transcriptomics, proteomics, biochemistry and live-cell super-resolution imaging in these perturbation contexts, we demonstrate that a strong increase in RNA molecules at enhancers disrupts their long-range interactions with gene promoters, whereas decreased RNA levels lead to stabilization of these interactions. Using separation-of-function perturbations, we show that this regulatory function of RNA is independent from the process of transcription and the proteins recruited to initiate transcription. Functionally, we show that RNA-mediated disruption of enhancer-promoter interactions is associated with reduced transcription of target genes, indicating a regulatory feedback mechanism. Together, our results uncover an additional regulatory principle of enhancer-promoter interactions mediated by non-coding RNA.

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Sagropoulou, S., Velychko, T., Laparra Cuervo, L., Stitzinger, S., Nicol, J., Walshe, J., Yan, Y., Ramasamy, S., tom Dieck, L., Bahr, F., Dybkov, O., Urlaub, H., Zumer, K., Lidschreiber, M., Oudelaar, A. M.. 2026-11-11. Non-coding RNA controls long-range enhancer-promoter interactions. https://doi.org/10.64898/2026.11.10.765568

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