RT Journal Article
SR Electronic
T1 HP1 oligomerization compensates for low-affinity H3K9me recognition and provides a tunable mechanism for heterochromatin-specific localization
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.26.428151
DO 10.1101/2021.01.26.428151
A1 Saikat Biswas
A1 Joshua D. Karslake
A1 Ziyuan Chen
A1 Ali Farhat
A1 Peter L. Freddolino
A1 Julie S. Biteen
A1 Kaushik Ragunathan
YR 2021
UL http://biorxiv.org/content/early/2021/05/17/2021.01.26.428151.abstract
AB HP1 proteins bind with low affinity but high specificity to histone H3 lysine 9 methylation (H3K9me), forming transcriptionally inactive genomic compartments referred to as heterochromatin. How HP1 proteins traverse a complex and crowded chromatin landscape on the millisecond timescale and yet recognize H3K9me with high specificity remains paradoxical. Here, we visualize the single-molecule dynamics of an HP1 homolog, the fission yeast Swi6, in its native chromatin environment. By analyzing the motions of individual Swi6 molecules, we identify mobility states that map to discrete biochemical intermediates. Using mutants that perturb Swi6 H3K9me recognition, oligomerization, or nucleic acid binding, we parse the mechanism by which each biochemical property affects protein dynamics. We find that rather than enhancing chromatin binding, nucleic acid interactions, compete with and titrates Swi6 away from heterochromatin. However, as few as four tandem Swi6 chromodomains are necessary and sufficient to restore H3K9me-dependent localization. Our studies propose propose that HP1 oligomerization stabilizes higher-order protein configurations of a defined stoichiometry that facilitates high-specificity H3K9me recognition and outcompetes the inhibitory effects of nucleic acid-binding.Competing Interest StatementThe authors have declared no competing interest.