Active Transcription and Epigenetic Reactions Synergistically Regulate Meso-Scale Genomic Organization

• DOI: 10.1101/2023.04.21.537822
• Publication Date: 2023-04-24T03:50:14Z
• Authors: Aayush Kant; Zixian Guo; Vinayak; Maria Victoria Ne...; Wing Shun Li; Vasundhara Agrawal; Emily Pujadas; Luay Almassalha; Vadim Backman; Melike Lakadamyali; Maria Pia Cosma; Vivek B. Shenoy
• Keywords: Euchromatin; Transcription; Nucleoplasm

Abstract In interphase nuclei, chromatin is organized into interspersed dense domains with characteristic sizes, both in the nuclear interior and periphery. However, quantitative impact of transcription histone modifications on size distribution these remains unclear. Here, we introduce a mesoscale theoretical model that investigates relationship between heterochromatic domain sizes loop extrusion rates from domains. The considers chromatin-chromatin chromatin-lamina interactions, methylation acetylation kinetics, diffusion epigenetic marks nucleoplasm. Our generates testable predictions help reveal biophysics underlying organization presence transcription-driven extrusion. This process kinetically captured through conversion heterochromatin to euchromatin response RNAPII activity. We discovered balance diffusive reactive fluxes governs steady-state Using theory simulations, predicted loss results increased compaction larger sizes. To validate our predictions, employed complementary super-resolution nano-imaging techniques five different cell lines impaired transcription. quantitatively assessed how scale at hetero-euchromatin interfaces. analysis previously obtained images nuclei revealed excessive leads smaller successfully recapitulated observations, explaining can counteract effects cohesin overloading. As general biophysical mechanisms regulating are independent type, findings have significant implications for understanding role global genome organization.