Torsional behaviour of supercoiled DNA regulates recognition of architectural protein Fis on minicircle DNA

Abstract

Three-dimensional genome organization is indispensable for regulating its functions. Experimental techniques based on the proximity ligation principle have identified spatially segregated domains at a sub-megabase level. The transcriptional activity of these domains is strongly coupled with the supercoiled DNA topology. The underlying molecular principle however remains unknown. By developing a computational framework, we investigate the differential kinetics of an architectural protein Fis on supercoiled DNA. We find that DNA supercoiling favours formation of juxtaposition sites where proteins can perform intersegmental transfer between the spatially close sites. The juxtaposition sites in positively supercoiled DNA are torsionally pinned that results in a slow protein diffusion on it, whereas the torsional behaviour of negatively supercoiled DNA ensures rapid protein-DNA communication and overall fast recognition of the cognate site by proteins. The result is robust for other proteins irrespective of their molecular features. Furthermore, our study suggests that variation in protein diffusivity on different supercoiled DNA also influences the shape of the latter. By unravelling the underlying molecular picture, our results unravel a plausible link between the degree of DNA supercoiling and the regulation of gene transcription that significantly advances the current understanding of the function and organization of chromatin inside cells.