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FRIMEDBIO-Fri prosj.st. med.,helse,biol

URGE-3D: Unraveling new gene dysregulation modules in cancer through integrated multi-constraint 3D genome modeling

Alternative title: URGE-3D: Identifikasjon av genreguleringsmoduler i kreft ved integrert 3D-genommodellering

Awarded: NOK 8.0 mill.

DNA is organized in three dimensions (3D) inside the cell nucleus. This organization is crucial for regulating how genes are turned on and off, and to maintain our cells' normal functions. However, knowledge of the relationships between the 3D organization of DNA and cell function is limited, and needs to be characterized further to understand and treat cancer cells, which often contain disorganized DNA. Thus, in this project we will develop high-resolution computational models of the 3D organization of DNA in normal and cancer cells. These models will be used to study DNA disorganization in 12 different cancer types by investigating how large, structural reorganizations ("translocations") can cause genes to be misplaced inside the cell nucleus. By combining biophysics modeling with live-cell imaging we will study how DNA 3D organization changes over time, giving insights into the dynamic processes that underly gene regulation in normal and disease states. Altogether, the project integrates knowledge and methods from biology, physics and informatics to exploit the great potential in a cross-disciplinary approach to study complex diseases like cancer. The outcome of the project will be new methods to understand the relationships between DNA 3D organization and gene regulation, and new knowledge on how such disorganization can lead to diseases such as cancer.

Deciphering 3D genome organization is one of the biggest challenges in the post-genomic era. Large international consortia are generating datasets at a rapid pace, coupling 3D genome information with epigenetic and transcriptomic information in normal and disease states. These "nucleome" data provide insight into genome organization in space and time, and are crucial to understand how our cells function. However, a key challenge remains: How can these data be integrated to unravel relationships between 3D genome organization and function? The URGE-3D project proposes solutions to this key challenge. The DNA in the nucleus is folded in three dimensions (3D). This folding is critical for the orchestration of gene expression during development, differentiation and tissue homeostasis, and for the balance between healthy and pathological states. However, most genomic information is only represented linearly on the chromosomes, limiting our ability to understand genome processes. To alleviate these limitations, the goal of URGE-3D is to generate novel computational models of the 3D genome opening up for new understanding of the structure-activity relationships of our genes in normal and disease states. I propose to develop an open-source multi-constraint 3D genome modeling tool from genome interactions with organizing nuclear bodies and structures. Chromosomal translocations in 12 different cancer types will be used to study effects of 3D repositioning of genes in the nucleus relative to nuclear bodies. Live-cell imaging and computational modeling will be integrated to understand the structural dynamics underlying gene expression regulation. Thus, this project combines cutting-edge biocomputation, biophysics and (live) microscopy imaging, and opens up new cross-disciplinary avenues with strong potential to improve our understanding of gene dysregulation in diseases such as cancer.

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Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

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