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Euchromatin is an accessible phase of genetic material containing genes that encode proteins with increased expression levels. The structure of euchromatin in vitro has been described as a 30-nm fiber formed from ordered nucleosome arrays. However, recent advances in microscopy have revealed an in vivo euchromatin architecture that is much more disordered, characterized by variable-length linker DNA and sporadic nucleosome clusters. In this work, we develop a theoretical model to elucidate factors contributing to the disordered in vivo architecture of euchromatin. We begin by developing a 1D model of nucleosome positioning that captures the interactions between bound epigenetic reader proteins to predict the distribution of DNA linker lengths between adjacent nucleosomes. We then use the predicted linker lengths to construct 3D chromatin configurations consistent with the physical properties of DNA within the nucleosome array, and we evaluate the distribution of nucleosome cluster sizes in those configurations. Our model reproduces experimental cluster-size distributions, which are dramatically influenced by the local pattern of epigenetic marks and the concentration of reader proteins. Based on our model, we attribute the disordered arrangement of euchromatin to the heterogeneous binding of reader proteins and subsequent short-range interactions between bound reader proteins on adjacent nucleosomes. By replicating experimental results with our physics-based model, we propose a mechanism for euchromatin organization in the nucleus that impacts gene regulation and the maintenance of epigenetic marks.
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Explicit ion modeling predicts physicochemical interactions for chromatin organization
Molecular mechanisms that dictate chromatin organization in vivo are under active investigation, and the extent to which intrinsic interactions contribute to this process remains debatable. A central quantity for evaluating their contribution is the strength of nucleosome-nucleosome binding, which previous experiments have estimated to range from 2 to 14kBT. We introduce an explicit ion model to dramatically enhance the accuracy of residue-level coarse-grained modeling approaches across a wide range of ionic concentrations. This model allows for de novo predictions of chromatin organization and remains computationally efficient, enabling large-scale conformational sampling for free energy calculations. It reproduces the energetics of protein-DNA binding and unwinding of single nucleosomal DNA, and resolves the differential impact of mono- and divalent ions on chromatin conformations. Moreover, we showed that the model can reconcile various experiments on quantifying nucleosomal interactions, providing an explanation for the large discrepancy between existing estimations. We predict the interaction strength at physiological conditions to be 9kBT, a value that is nonetheless sensitive to DNA linker length and the presence of linker histones. Our study strongly supports the contribution of physicochemical interactions to the phase behavior of chromatin aggregates and chromatin organization inside the nucleus.
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- Award ID(s):
- 2042362
- PAR ID:
- 10559038
- Publisher / Repository:
- Elife
- Date Published:
- Journal Name:
- eLife
- Volume:
- 12
- ISSN:
- 2050-084X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.7554/eLife.90073
