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Release of linker histone from the nucleosome driven by polyelectrolyte competition with a disordered protein

Abstract

Highly charged intrinsically disordered proteins are essential regulators of chromatin structure and transcriptional activity. Here we identify a surprising mechanism of molecular competition that relies on the pronounced dynamical disorder present in these polyelectrolytes and their complexes. The highly positively charged human linker histone H1.0 (H1) binds to nucleosomes with ultrahigh affinity, implying residence times incompatible with efficient biological regulation. However, we show that the disordered regions of H1 retain their large-amplitude dynamics when bound to the nucleosome, which enables the highly negatively charged and disordered histone chaperone prothymosin α to efficiently invade the H1–nucleosome complex and displace H1 via a competitive substitution mechanism, vastly accelerating H1 dissociation. By integrating experiments and simulations, we establish a molecular model that rationalizes the remarkable kinetics of this process structurally and dynamically. Given the abundance of polyelectrolyte sequences in the nuclear proteome, this mechanism is likely to be widespread in cellular regulation.

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Fig. 1: H1 binds nucleosomes tightly but reversibly.
Fig. 2: H1 binds nucleosomes with diffusion-limited association rates.
Fig. 3: ProTα facilitates H1 dissociation from the nucleosome.
Fig. 4: H1 remains disordered and dynamic on the nucleosome.
Fig. 5: Mechanism of H1 chaperoning on the nucleosome by ProTα.

Data availability

Data supporting the findings of this study are available within the paper and its Supplementary Information. Source data are provided with this paper.

Code availability

A custom WSTP add-on for Mathematica (Wolfram Research) used for the analysis of single-molecule fluorescence data is available upon request and at https://schuler.bioc.uzh.ch/programs. A modified version of GROMACS was used for coarse-grained simulations, which is available at https://github.com/bestlab/gromacs-2019.4.git.

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Acknowledgements

We thank I. König for providing ProTα, K. Buholzer and F. Sturzenegger for helpful discussion, F. Büchler and N. Wyss for excellent technical assistance and the Functional Genomics Center Zurich for performing mass spectrometry. This work utilized the computational resources of the National Institutes of Health HPC Biowulf cluster (http://hpc.nih.gov) and of Piz Daint at the CSCS Swiss National Supercomputing Centre. This project was funded by the Novo Nordisk Foundation (P.O.H.), the Carlsberg Foundation (P.O.H.), The Boehringer Ingelheim Fonds (S.K.), the Swiss National Science Foundation (B.S. and B.F.), École Polytechnique Fédérale de Lausanne (B.F.) and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (R.B.B.).

Author information

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Authors

Contributions

P.O.H., D.M., R.B.B. and B.S. designed the research; P.O.H. and S.K. prepared the reconstituted nucleosomes; P.O.H., M.B.B., A.B., A.S., S.K. and B.F. prepared the fluorescently labelled and/or unlabelled proteins; P.O.H. and A.S. performed the single-molecule experiments; P.O.H., A.S., D.N. and B.S. analysed the single-molecule data; D.M. and R.B.B. performed and analysed the simulations; R.B.B., B.F. and B.S. supervised the research; and P.O.H. and B.S. wrote the paper with help from all authors.

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Correspondence to Pétur O. Heidarsson, Robert B. Best or Benjamin Schuler.

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Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–7, Tables 1–3 and references.

Reporting Summary

Supplementary Video 1

Ensemble of H1 bound to the nucleosome. H1 is represented in blue, DNA in grey and the core histones in white. The video shows 1,000 conformers of the H1–nucleosome complex, obtained from replica-exchange molecular dynamics simulations as described in the Methods.

Supplementary Video 2

Binding and dissociation trajectories of ProTα and H1 bound to the nucleosome. ProTα is shown in red, H1 in blue, DNA in grey and the core histones in white. The trajectory depicting the association of ProTα to the H1–nucleosome complex is concatenated with a trajectory showing the ProTα–H1 complex dissociating from the nucleosome (as indicated by the text displayed), where a ratchet bias with a force constant of 1 kJ mol−1 nm−2 is applied to the globular domain with respect to the dyad to enable dissociation during the accessible simulation time. The segments of the simulations shown correspond to ~5.0 × 105 time steps for ProTα binding and ~2 × 105 time steps for dissociation. Note that these times are more akin to transition path times for binding and dissociation than first passage times, which would be orders of magnitude longer.

Supplementary Data

Source data supporting information.

Source data

Source Data Fig. 1

Transfer efficiency histograms, binding isotherms and binding affinities.

Source Data Fig. 2

Fluorescence time trajectory, dwell times and association/dissociation rates.

Source Data Fig. 3

Fluorescence time trajectories, association/dissociation rates, transfer efficiency histograms and binding isotherms.

Source Data Fig. 4

The nsFCS data, transfer efficiency histograms and transfer efficiencies from experiment and simulation.

Source Data Fig. 5

Simulation data.

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Heidarsson, P.O., Mercadante, D., Sottini, A. et al. Release of linker histone from the nucleosome driven by polyelectrolyte competition with a disordered protein. Nat. Chem. 14, 224–231 (2022). https://doi.org/10.1038/s41557-021-00839-3

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