ATP-dependent chromatin remodellers have central roles in eukaryotic gene regulation, development and disease. Some remodellers regulate gene expression in a gene- or cell-type-specific manner, presumably through recruitment to specific promoters and enhancers. Because chromatin remodellers generally lack intrinsic DNA-sequence specificity, how they target specific genes has been a fundamental question since the early days of the field. Classical genetic and biochemical studies of SWI/SNF and related complexes established the general idea that remodellers can be recruited by transcription factors (TFs), but the molecular basis often remained obscure. These questions are inherently difficult to address because many chromatin remodellers are large, multi-subunit complexes, whereas TF regulatory domains can be highly unstructured, promiscuous in their interactions, and only weakly conserved across evolution.

In 2021, Donovan et al. published a study on DNA specificity of chromatin remodellers that was particularly illuminating. Working in budding yeast (in vivo), the authors showed that the ISWI-family remodeller Isw2 is not simply a generic nucleosome-spacing machine. Instead, Isw2 behaves as an obligately targeted remodeller whose action depends on direct interaction with a sequence-specific TF, Ume6. Genome-wide nucleosome profiling showed that Isw2 acts at specific loci and primarily repositions a single nucleosome adjacent to a bound TF, rather than organizing long arrays non-specifically across chromatin. That observation alone challenges the prevailing view of ISWI enzymes as largely promiscuous spacers in cells.