Descripción del proyecto
Interconexión entre la estructura cromosómica espacial y la función
La estructura espacial del genoma es crucial para su función biológica. El objetivo del proyecto LoopingDNA, financiado con fondos europeos, es comprender la interconexión fundamental entre la estructura y la función de los cromosomas a través de un método biofísico. La investigación se centrará en los complejos proteicos de mantenimiento estructural de los cromosomas (SMC, por sus siglas en inglés), proteínas con forma de anillo que crean grandes bucles de ADN que, según se cree, son la base de la estructura cromosómica. Los experimentos ayudarán a responder preguntas abiertas sobre cómo los complejos proteicos de SMC gestionan las fibras cromosómicas naturales cargadas con proteínas de unión al ADN y regulan la expresión génica. Los investigadores incluso intentarán crear un cromosoma con un enfoque ascendente, utilizando un método de «genoma en una caja», en el que a un ADN desnudo de la longitud del genoma se agregue complejos proteicos de SMC y otras proteínas de procesamiento de ADN. Este planteamiento ascendente único puede proporcionar datos totalmente nuevos sobre las fuerzas físicas y los sistemas proteicos que conforman los cromosomas.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
2628 CN Delft
Países Bajos