Project description
Interconnection of spatial chromosome structure and function
The spatial structure of the genome is critical for its biological function. The goal of the EU-funded LoopingDNA project is to understand the fundamental interconnection of structure and function of chromosomes using a biophysics approach. Research will focus on structural maintenance of chromosomes' (SMC) protein complexes, ring-shaped proteins that create large loops of DNA thought to be the basis of chromosome structure. The experiments will help answer open questions of how SMCs handle natural chromosomal fibres loaded with DNA-binding proteins and regulate gene expression. The researchers will even aim to build a chromosome from the bottom up, using a ‘genome-in-a-box’ approach, where a genome-length bare DNA is added SMC protein complexes and other DNA-processing proteins. This unique bottom-up approach may generate a radically new understanding of the physical forces and protein systems that shape chromosomes.
Objective
How is DNA spatially organized in our cells? What are the mechanisms that shape chromosomes and how does their 3D architecture direct their function? Recent years have shown that the spatial structure of the genome is of pivotal importance for its biological function. Yet, the basic physics of the formation and regulation of its 3D structure has remained unclear. This proposal aims to understand the fundamental structure of chromosomes using a bottom up biophysics approach, from looping at the single-molecule level to higher levels of complexity. We focus on so-called SMC protein complexes (SMC = Structural Maintenance of Chromosomes). These ring-shaped proteins are a unique new type of molecular motors that can extrude large loops of DNA that are thought to be the basis of chromosome structure. Our group’s recent breakthrough discovery of the looping motor function of condensin SMC paved the way to now answer major open questions, such as the motor mechanism of SMCs; how SMCs handle realistic chromosomal fibers loaded with DNA-binding proteins; how looping relates to gene expression; and whether it is evolutionary conserved from bacteria to man. By answering these questions using single-molecule assays, we will resolve the basic mechanics of the SMC-induced looping of DNA. We will extend this to even build a chromosome from the bottom up, in a ‘genome-in-a-box’ approach where we will take genome-length bare DNA and add SMC protein complexes and other DNA-processing proteins. Such a well-controlled bottom-up approach – which to our knowledge is unique – can be expected to generate a radically new understanding of the physical forces and protein systems that shape chromosomes. We are confident that our powerful single-molecule biophysics tools, in collaboration with working with the world’s best biochemists, will enable to disentangle the fundamental looping architecture of chromosomes that is so essential to all of life.
Fields of science
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
2628 CN Delft
Netherlands