Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA

Abstract

ATP-dependent chromatin remodelers control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication.Here, we investigate the mechanism of active DNA sliding by remodelers, which underlies most remodeling functions, via molecular dynamics simulations of the Snf2 remodeler in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the remodeler overwrites the original nucleosome energy landscape via steric and electrostatic interactions to induce sliding of nucleosomal DNA. Repositioning is initiated at the remodeler binding location via the generation of twist defects, which then spontaneously propagate to complete sliding throughout the entire nucleosome. We also reveal how remodeler mutations and DNA sequence control active nucleosome repositioning. These results offer a mechanistic understanding of chromatin remodeling important for the interpretation of experimental studies.Although the changes in chromatin organization induced by remodelers have been widely documented 2,10,14 , the precise molecular mechanisms are still far from being clear 11,12,20 . The complexity comes in part from the existence of a wide variety of remodelers with different structures and functions 11 , which has led to several possible classifications into remodeler sub-families 21 . Each remodeler consists of many distinct domains, which act in concert to confer specificity to the remodeling activity (e.g. nucleosome sliding vs ejection) 11,12 and to fine-tune it via substrate recognition (e.g. of histone tail modifications) 21,22 . Despite this complexity, all remodelers share a conserved translocase domain 11 : an ATPase motor capable of unidirectional sliding along DNA via binding and hydrolysis of ATP between its two RecA-like lobes, structurally similar to those found in helicases 11,12,21 . The translocase domain of most remodelers binds nucleosomes at the superhelical location (SHL) 2 11,23,24 , i.e. two DNA turns away from the dyad symmetry axis (SHL 0) 25 (Fig. 1a). Remodelers induce sliding of nucleosomal DNA towards the dyad from the translocase binding location 11,26 . This may represent a shared fundamental mechanism at the basis of all remodeling activities; the interactions with the additional domains would then confer specificity to the remodeler, allowing for substrate recognition and determining whether the final outcome is nucleosome repositioning, histone ejection or histone exchange 11 .There is much experimental evidence suggesting that the translocase domain in remodelers, as well as some helicases, slides unidirectionally along DNA via an inchworm mechanism 11,27 (sometimes referred as ratchet 24,28 ), processing by 1 bp every ATP cycle. A minimal inchworm model requires 3 distinct chemical states, apo, ATP-bound, and ADP-bound, which are coupled to conformational changes of the translocase (Fig. 1b).The two lobes are either distant in the open form or in contact in the closed form...

Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations

“…Binding of two remodeler molecules could allow for higher efficiency in positioning the nucleosome at a precise location but necessitates coordination of the remodellers. A possible mechanism for coordination could be that twist defects that are introduced by remodeler binding are propagated from the entry SHL 2 into the exit side SHL 2 ( Brandani et al, 2018 ; Brandani and Takada, 2018 ). Presence of the twist defect at the second remodeler binding site could interfere with the translocation activity of the second remodeler ( Sabantsev et al, 2019 ).…”

Nucleosomal DNA dynamics mediate Oct4 pioneer factor binding

“…Therefore, questions that require longer and a higher number of simulations can be addressed. As a result, models of sequence-specific nucleosome dynamics, revealing the role of the sequence in nucleosome breathing and unwrapping 22,28 , or protein-mediated remodeling 29 have been established. However, the descriptions obtained from coarse grained simulations is limited because important details regarding the interactions that modulate nucleosome dynamics are missing.…”

Inchworm stepping of Myc-Max heterodimer protein diffusion along DNA

“…The two BRs of the Myc-Max heterodimer alternate stepping on the DNA, transiting between a closed and an open conformation, i.e., the leading BR steps first (from the closed to open) and the trailing BR follows (open to closed). Such inchworm stepping motions have been identified previously in nucleic acid molecular motors such as PcrA helicase [50,51] and chromatin remodeler [52]. In PcrA helicase, for example, domain 1A and 2A alternative their affinities with the single-stranded (ss)DNA, in coordination with ATP binding and product release cycles, so that the helicase moves directionally via the inchworm motions along ssDNA [50,51].…”