Megadalton chromatin remodelers: common principles for versatile functions

•cryo-EM structures of all four families of ATP-dependent chromatin remodelers.•A common architecture of multi-subunit remodelers.•A unified motor, rotor, stator and grip mechanism for large scale nucleosome reconfigurations.•A molecular function of nuclear actin for allosteric regulation of remodelers. ATP-dependent chromatin remodelers are enigmatic macromolecular machines that govern the arrangement and composition of nucleosomes across eukaryotic genomes. Here, we review the recent breakthrough provided by cryo-electron microscopy that reveal the first high-resolution insights into all four families of remodelers. We highlight the emerging structural and mechanistic principles with a particular focus on multi-subunit SWI/SNF and INO80/SWR1 complexes. A conserved architecture comprising a motor, rotor, stator and grip suggests a unifying mechanism for how stepwise DNA translocation enables large scale reconfigurations of nucleosomes. A molecular circuitry involving the nuclear actin containing module establishes a framework for understanding allosteric regulation. Remodelers emerge as programable hubs that enable differential processing of genetic and epigenetic information in response to the physiological state of a cell.