Active transcription and epigenetic reactions synergistically regulate meso-scale genomic organization

Aayush Kant, Zixian Guo, Vinayak Vinayak, Maria Victoria Neguembor, Wing Shun Li, Vasundhara Agrawal, Emily Pujadas, Luay Almassalha, Vadim Backman, Melike Lakadamyali, Maria Pia Cosma and Vivek B. Shenoy ()
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Aayush Kant: University of Pennsylvania
Zixian Guo: University of Pennsylvania
Vinayak Vinayak: University of Pennsylvania
Maria Victoria Neguembor: The Barcelona Institute of Science and Technology
Wing Shun Li: Northwestern University
Vasundhara Agrawal: Northwestern University
Emily Pujadas: Northwestern University
Luay Almassalha: Northwestern University
Vadim Backman: Northwestern University
Melike Lakadamyali: University of Pennsylvania
Maria Pia Cosma: The Barcelona Institute of Science and Technology
Vivek B. Shenoy: University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract In interphase nuclei, chromatin forms dense domains of characteristic sizes, but the influence of transcription and histone modifications on domain size is not understood. We present a theoretical model exploring this relationship, considering chromatin-chromatin interactions, histone modifications, and chromatin extrusion. We predict that the size of heterochromatic domains is governed by a balance among the diffusive flux of methylated histones sustaining them and the acetylation reactions in the domains and the process of loop extrusion via supercoiling by RNAPII at their periphery, which contributes to size reduction. Super-resolution and nano-imaging of five distinct cell lines confirm the predictions indicating that the absence of transcription leads to larger heterochromatin domains. Furthermore, the model accurately reproduces the findings regarding how transcription-mediated supercoiling loss can mitigate the impacts of excessive cohesin loading. Our findings shed light on the role of transcription in genome organization, offering insights into chromatin dynamics and potential therapeutic targets.

Date: 2024
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DOI: 10.1038/s41467-024-48698-z

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