Sustained MYB activity drives emergent enhancer activation and precise enhancer-promoter interactions

Lau, I.-J.; Harman, J. R.; Smith, A. L.; Denny, N.; Jackson, N. E.; Hamley, J. C.; Vyas, P.; Davies, J. O. J.; Hughes, J. R.; Crump, N. T.; Milne, T. A.

doi:10.1101/2025.04.16.649256

bioRxiv · 10.1101/2025.04.16.649256

Sustained MYB activity drives emergent enhancer activation and precise enhancer-promoter interactions

Lau, I.-J.·Harman, J. R.·Smith, A. L.·Denny, N.·Jackson, N. E.·Hamley, J. C.·Vyas, P.·Davies, J. O. J.·Hughes, J. R.·Crump, N. T.·Milne, T. A.

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Abstract

Transcription factors (TFs) are key effectors of enhancer activity. MYB is a critical hematopoietic TF that is frequently dysregulated in cancer. Despite its well-established role, the exact mechanisms by which MYB influences enhancer function--and the specific stages of enhancer activation at which it operates--remain poorly understood. Using high resolution Micro-Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at specific MYB binding sites are lost. Loss of these interactions, together with other hallmarks of enhancer activity--reduced H3 lysine-27 acetylation and enhancer RNA transcription--correlates with significant downregulation of target gene expression in leukemia, indicating that MYB mediates transcription activation via maintenance of enhancer function. When anchored to DNA within a gene desert region that is devoid of histone marks and active transcription, the MYB transactivation domain is sufficient and necessary for the nucleation of an enhancer-like region. This results in the activation of transcription from distal cryptic elements and the establishment of long-range chromatin interactions up to 400 kb away from the anchor point. Together, these results indicate that MYB activity alone is sufficient to induce long-range interactions and transcription, achieving this through highly precise enhancer-promoter crosstalk.

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Lau, I.-J., Harman, J. R., Smith, A. L., Denny, N., Jackson, N. E., Hamley, J. C., Vyas, P., Davies, J. O. J., Hughes, J. R., Crump, N. T., Milne, T. A.. 2025-04-22. Sustained MYB activity drives emergent enhancer activation and precise enhancer-promoter interactions. https://doi.org/10.1101/2025.04.16.649256

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