Genome control by DNA-looping motors: from folding to function

forthcoming

Our genome is not merely an information code but also a physical object: a long polymer of DNA with a dynamic three-dimensional organisation that is crucial for its function. Recently, we and others discovered that SMC protein complexes are a novel class of remarkable molecular motors that extrude loops of DNA. While insights into how this motor activity shapes chromosomes are revolutionising our understanding of chromosome structure, it is becoming clear that SMC motors are also key to controlling the expression of genetic information – a core function of cells. GeneMotors seeks to tackle the grand challenge of understanding how the tiny SMC motors orchestrate functions of a huge genome. Understanding how SMC motors work and regulate biological functions addresses long-standing puzzles in genetics such as how invading viral genes are silenced or how regulatory information in the non-coding, so-called 'dark matter', 98% of the genome reaches out to genes to control their expression. To settle this, we aim to 1) unravel the basic molecular motor mechanism of the DNA-looping SMCs and their collective behaviour, 2) disentangle the ‘control knobs’ that regulate their use in cellular processes, and 3) resolve how DNA looping by SMCs promotes gene regulation through long-distance communication along the genome. This ambitious program transcends the boundaries of any single discipline. Our team unites cutting-edge cell biology with single-molecule biophysics and modelling from the atomic to chromosome level. This unique combination of expertise across scales enables to resolve questions about how detailed molecular mechanisms have functional consequences for the complexity of the mammalian genome – achieving together what we cannot do alone. Showing how these SMC motors regulate the huge genome will impact fields from molecular motors to genetics and developmental biology, sparking advances that are likely to reshape our understanding of human development and disease.