Kant, AayushGuo, ZixianVinayak, VinayakNeguembor, Maria VictoriaLi, Wing ShunAgrawal, VasundharaPujadas, EmilyAlmassalha, LuayBackman, VadimLakadamyali, MelikeCosma, Maria PiaShenoy, Vivek B.2024-09-062024-09-062024Kant A, Guo Z, Vinayak V, Neguembor MV, Li WS, Agrawal V, et al. Active transcription and epigenetic reactions synergistically regulate meso-scale genomic organization. Nat Commun. 2024 May 21;15(1):4338. DOI: 10.1038/s41467-024-48698-z2041-1723http://hdl.handle.net/10230/61030In 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.application/pdfeng© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-024-48698-zBiological physicsComputational biophysicsSuper-resolution microscopyinfo:eu-repo/semantics/openAccess