How does CHD4 slide nucleosomes?

Chromatin remodelling enzymes reposition nucleosomes throughout the genome to regulate the rate of transcription and other processes. These enzymes have been studied intensively since the 1990s, and yet the mechanism by which they operate has only very recently come into focus, following advances in cryoelectron microscopy and single-molecule biophysics. CHD4 is an essential and ubiquitous chromatin remodelling enzyme that until recently has received less attention than remodellers such as Snf2 and CHD1. Here we review what recent work in the field has taught us about how CHD4 reshapes the genome. Cryoelectron microscopy and single-molecule studies demonstrate that CHD4 shares a central remodelling mechanism with most other chromatin remodellers. At the same time, differences between CHD4 and other chromatin remodellers result from the actions of auxiliary domains that regulate remodeller activity by for example: (1) making differential interactions with nucleosomal epitopes such as the acidic patch and the N-terminal tail of histone H4, and (2) inducing the formation of distinct multi-protein remodelling complexes (e.g. NuRD vs ChAHP). Thus, although we have learned much about remodeller activity, there is still clearly much more waiting to be revealed.

A NuRD for all seasons.

The nucleosome-remodeling and deacetylase (NuRD) complex is an essential transcriptional regulator in all complex animals. All seven core subunits of the complex exist as multiple paralogs, raising the question of whether the complex might utilize paralog switching to achieve cell type-specific functions. We examine the evidence for this idea, making use of published quantitative proteomic data to dissect NuRD composition in 20 different tissues, as well as a large-scale CRISPR knockout screen carried out in >1000 human cancer cell lines. These data, together with recent reports, provide strong support for the idea that distinct permutations of the NuRD complex with tailored functions might regulate tissue-specific gene expression programs.

The role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families.

CHD4 is an essential, widely conserved ATP-dependent translocase that is also a broad tumour dependency. In common with other SF2-family chromatin remodelling enzymes, it alters chromatin accessibility by repositioning histone octamers. Besides the helicase and adjacent tandem chromodomains and PHD domains, CHD4 features 1000 residues of N- and C-terminal sequence with unknown structure and function. We demonstrate that these regions regulate CHD4 activity through different mechanisms. An N-terminal intrinsically disordered region (IDR) promotes remodelling integrity in a manner that depends on the composition but not sequence of the IDR. The C-terminal region harbours an auto-inhibitory region that contacts the helicase domain. Auto-inhibition is relieved by a previously unrecognized C-terminal SANT-SLIDE domain split by ~150 residues of disordered sequence, most likely by binding of this domain to substrate DNA. Our data shed light on CHD4 regulation and reveal strong mechanistic commonality between CHD family members, as well as with ISWI-family remodellers.