The mechanisms of action of chromatin remodelers and implications in development and disease

Abstract

The eukaryotic genetic material is packaged in the form of chromatin by wrapping DNA around nucleosomes. Cells maintain chromatin in a dynamic state by utilising various ATP-dependent chromatin remodelling complexes which can induce structural transformations in the chromatin. All chromatin remodelers contain an ATP hydrolysing-DNA translocase motor which facilitates nucleosomal DNA translocation. By DNA translocation ISWI and CHD subfamily remodelers slide nucleosomes and arrange them in a regularly spaced array. While SWI/SNF subfamily remodelers evict or displace nucleosomes from chromatin, which promotes recruitment of transcription machinery and DNA repair factors on the DNA. Besides DNA translocation, ISWI, CHD and INO80 subfamily remodelers escort nucleosome organisation and editing. In this review; we discuss different mechanisms by which chromatin remodelers regulate chromatin accessibility, nucleosome assembly and nucleosome editing. We attempt to elucidate how their action mediates various cellular and developmental processes, and their deregulation leads to disease pathogenesis. We emphasised on their role in cancer progression and potential therapeutic implications of these complexes. We also described the drugs and strategies which are being developed to target different subunits of remodelling complexes, histone modifying enzymes and polycomb repressive complex. This includes ATPase inhibitors, EZH2 (enhancer of zeste homolog 2) inhibitors, BET (bromodomain and extra terminal) inhibitors, PROTAC (proteolysis targeting chimaera) and inhibitors of protein-protein interaction.

Keywords: ATP-dependent chromatin remodelers; CHD; Chromatin remodelling; INO80; ISWI; SWI/SNF.