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Emergence of chromatin hierarchical loops from protein disorder and nucleosome asymmetry

Significance Inside eukaryotic cells, DNA is organized in the form of chromatin. Protein disorder is abundant both within the chromatin-building blocks—the nucleosomes—and the regulatory chromatin-binding proteins. Such protein disorder facilitates transient and nonspecific binding of a wide-range of proteins to the nucleosomes and favors heterogeneity of nucleosome-nucleosome interactions. Here, we reveal additional important roles of protein disorder in chromatin structure regulation: symmetry breaking of the nucleosome-building blocks, enhancement of linker DNA fluctuations, and encouragement of chromatin structural fluidity and long-range regulatory loops. More broadly, our results demonstrate that chromatin-binding proteins can remain disordered or partially disordered when binding to and stabilizing the chromatin fiber. Protein flexibility and disorder is emerging as a crucial modulator of chromatin structure. Histone tail disorder enables transient binding of different molecules to the nucleosomes, thereby promoting heterogeneous and dynamic internucleosome interactions and making possible recruitment of a wide-range of regulatory and remodeling proteins. On the basis of extensive multiscale modeling we reveal the importance of linker histone H1 protein disorder for chromatin hierarchical looping. Our multiscale approach bridges microsecond-long bias-exchange metadynamics molecular dynamics simulations of atomistic 211-bp nucleosomes with coarse-grained Monte Carlo simulations of 100-nucleosome systems. We show that the long C-terminal domain (CTD) of H1—a ubiquitous nucleosome-binding protein—remains disordered when bound to the nucleosome. Notably, such CTD disorder leads to an asymmetric and dynamical nucleosome conformation that promotes chromatin structural flexibility and establishes long-range hierarchical loops. Furthermore, the degree of condensation and flexibility of H1 can be fine-tuned, explaining chromosomal differences of interphase versus metaphase states that correspond to partial and hyperphosphorylated H1, respectively. This important role of H1 protein disorder in large-scale chromatin organization has a wide range of biological implications.