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Higher order from high disorder: DNA condensation by linker histone tails

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Disordered proteins play an essential role in a wide variety of biological processes. One such protein is Histone H1, which condenses chromatin – the complex of genomic DNA and its packaging proteins – in a way that is still poorly understood, despite decades of research. While the textbooks tell us that the endpoint of this condensation process is a 30 nm fibre, the fibre is elusive in vivo. Instead, the latest super-resolution methods reveal a heterogeneous, dynamic and liquid-like assembly, and the growing evidence, from us and others, points to liquid-liquid phase separation as a mechanism that could produce a compact but dynamic ‘ground state’ of H1-bound chromatin. The hypothesis is compelling, since a liquid condensate is a more plausible means by which chromatin could respond quickly to environmental stimuli.

The region of H1 that is responsible for chromatin condensation is its long, highly disordered C-terminal tail. However, the tail is all but invisible in the best cryo-EM structures of chromatin to date, implying some degree of disorder remains. We have developed a model system that is amenable to NMR and other biophysical techniques. The model allows us to study the nature of this disordered state at high resolution. In addition, it recapitulates the condensing behaviour of chromatin, forming phase-separated liquid condensates, while allowing capture of the thermodynamics underpinning the various processes. Before condensation, we find the protein, despite its high affinity for DNA , does not undergo a disorder-to-order transition on binding, but forms a ‘fuzzy complex’. We can also use the model to study the phase-separated state, which under certain conditions contains higher-order structure. The condensate is also highly sensitive to the phosphorylation state of the protein. These ‘bottom-up’ findings are broadly consistent with the current in vivo picture. They also provide insights into how tight binding need not be driven by disorder-to-order transitions, and how condensation and higher-order structuring can be dynamic and thus exquisitely sensitive to perturbation by post-translational modifications, broadening the repertoire of mechanisms that might regulate chromatin and presumably other macromolecular assemblies.

Turner AL, Watson M, Wilkins OG, Cato L, Travers A, Thomas JO, Stott K. “Highly disordered histone H1-DNA model complexes and their condensates.” Proc Natl Acad Sci U S A . (2018) doi: 10.1073/pnas.1805943115. Associated commentary:

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