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Unraveling supra-nucleosomal physical interactions that govern global transcription activity

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The role of nuclei nanoenvironment in cellular function has been a challenging problem in biology due to the lack of chromatin 3-dimension (3D) structure imaging/capturing techniques and theory connecting physical structure of chromatin to transcription. Recent studies on optical properties measurement on biological sample techniques, nanoscale imaging techniques and chromatin 3D structure techniques unraveled the important role of chromatin structure in regulating cellular functions, especially transcription. Leveraging Molecular Dynamics (MD) simulation, Brownian Dynamics (BD) simulation, system biology and power law scaling nature of chromatin, we developed the computational and theoretical model describing the mechanisms of modulating global patterns in the gene expression through the regulation of chromatin nanoenvironment, e.g. the scaling of chromatin packing (CP) and macromolecular crowding (MC) model. The CP-MC model describes the gene transcription as a function of the physical nanoenvironment, showing a good match with experiment results from RNA sequencing techniques, suggesting the existence of a pathway-independent global chromatin scaling “code” that governs the stochastic variations in gene expression by acting directly on physical factors such as gene accessibility, binding affinities, and transcription factor diffusion. Herein, we studied how various physical factors, including average nuclear density, the scaling of chromatin packing, gene length, and the upper length-scale of chromatin packing influence gene expression. Utilizing the CP-MC model, we identified a major functional role of the chromatin physical nanoenvironment as a regulator of cellular transcriptional responsiveness, which indicates the potential of a new field of engineering macrogenomic information space. As suggested by the idea of macrogenomic engineering, we developed the procedure of identifying compounds that target the packing of chromatin to enhance chemotherapeutic efficacy – Chromatin Protection Therapies (CPTs). Furthermore, we identify, both computationally and experimentally, the chromatin nanoenvironment as a key regulator of phenotypic plasticity by controlling both intercellular transcriptional heterogeneity and transcriptional malleability. We found that a higher scaling of chromatin packing produces a “tailwind effect” that amplifies the rate of gene transcription in response to external stimuli, possibly augmenting the ability of cells to adapt to cytotoxic stressors. Finally, analyzing transcriptional data from patients with advanced lung, colorectal and breast cancer, we identify an inverse relationship between patient survival and phenotypic plasticity.

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