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3DGENOME — Result In Brief

Project ID: 503441
Country: Netherlands

Folding - the new dimension of genome research

Gene transcription is one of the most important research areas in genomics today. A European project has revealed the impact of chromosome folding on how genes are turned on.
Folding - the new dimension of genome research
Each of our cells contains a staggering 2 metres of DNA thread in a nucleus of 0.001 mm diameter. The only way nature can achieve this is by its normal approach, folding. It appears that folding is important to how a cell activates and deactivates genes, and therefore how the cell operates.

The '3D Genome structure and function' (3DGenome) project aimed to produce a three-dimensional (3D) map of the folding of the DNA fibre inside the interphase nucleus of the human cell cycle. Folding patterns can then be related to gene activity.

Concentrating on certain chromosomes, the 3DGenome team used fluorescent in situ hybridisation (FISH) in combination with advanced 3D light microscopy. The scientists studied the relative position of genes in the folded structure irrespective of cell type, differentiation state and gene expression pattern.

A major challenge was to analyse the large number of images given the inherent variation in chromatin structure from cell to cell. The scientists developed new methods, software and technologies to overcome this obstacle.

Automation for classic and spinning disk confocal imaging was implemented. The massive amount of microscopy-based data sets presented problems with storage, analysis and interpretation. The scientists responded with new protocols and the establishment of an efficient image database as well as a fresh approach to quantitative analysis.

Findings showed that the chromatin of individual chromosomes folds to form different subchromosomal domains. The structure of these domains depends on variables like gene density and average levels of expression.

The position of the different domains is dependent on their level of transcription. Those that are more active and gene-dense are closer to the nucleus core and those that are sparse in genes and with lower transcription levels are closer to the nuclear membrane.

Overall, 3DGenome have identified a number of 3D folding principles that are closely related to the arrangement of genes on the DNA strand. This represents a solid foundation to integrate the influence of chromosome folding on gene transcription.

3DGenome results have enormous application potential in the field of genomics. The importance of the research is reflected in the number of publications arising – 49 to date in international scientific journals. A total of 124 seminars on 3DGenome research have been presented at conferences and workshops.

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