Emergence of chromatin hierarchical loops from protein disorder and nucleosome asymmetry

Akshay Sridhar, Stephen E. Farr, Guillem Portella, Tamar Schlick, Modesto Orozco, Rosana Collepardo-Guevara

Research output: Contribution to journalArticlepeer-review

Abstract

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 nucleosomebinding 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 largescale chromatin organization has a wide range of biological implications.

Original languageEnglish (US)
Pages (from-to)7216-7224
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number13
DOIs
StatePublished - Mar 31 2020

Keywords

  • CTD of H1
  • Chromatin polymorphism
  • H1-nucleosome binding
  • Nucleosome asymmetry
  • Protein disorder

ASJC Scopus subject areas

  • General

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