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3DGENOME Report Summary

Project ID: 503441
Country: Netherlands

Final Report Summary - 3DGENOME (3D Genome structure and function)

The human cell orchestrates the activity of its about 25 000 genes in an extremely efficient and reliably way. These genes are bits of genetic information on the deoxyribonucleic acid (DNA). Each of our cells contains DNA molecules with a total length of 2 meters, folded inside a cell nucleus of only 1/100th of a millimetre diameter. This is comparable to packing 20 km of thin wire inside a tennis ball. Evidently, the DNA thread is extremely folded inside a cell. This folding plays an important role in how a cell switches genes on and off, thereby determining how the cell behaves.

For instance, folding determines whether a cell becomes a skin cell, a liver cell or a neuron, and whether a cell is healthy or sick. Using advanced microscopy techniques in combination with novel image and data analysis software, the 3DGENOME project intended to establish a three-dimensional (3D) map of the folding of the DNA fibre inside the human cell. This folding map will be related to the pattern of active and inactive genes along the DNA fibre.

The aim of the 3DGENOME project was to analyse the 3D folding of the chromatin fibre inside the interphase nucleus, and unveil the relationship between the now well-established one-dimensional structure of the human genome (i.e. the nucleotide sequence) with its 3D folding inside the nucleus. The team concentrated collective efforts on a limited number of human chromosomes. Results of these studies offered new insight in the spatial organisation of the human genome in the cell. Basic principles were identified, which are independent of cell type and differentiation state and gene expression pattern. These add up to known dynamic aspects of chromatin structure that depend on gene activity.

In brief, findings showed that the chromatin of individual chromosomes folds to form different domains subchromosomal domains. The structure of these domains depend on parameters like gene density and average expression levels. Strikingly, these subchromosomal domains have different positions in the chromosome territory: transcriptionally highly active and gene-dense domains are positioned closer to the centre of the nucleus, whereas gene-poor, lowly expressed domains are located more closely to the nuclear envelope.

Biological efforts to analyse chromatin structure were paralleled by efforts to develop and employ new methods, technologies and software to 3D image chromatin structure and analyse data sets based on large number of such images. Given the inherent cell-to-cell variation in chromatin structure, this was a major challenge.

High-resolution microscopy techniques and protocols were developed. Application on the true biological systems was tricky due to various unexpected aspects of the system. Among others, probes to visualise genomic sequences by fluorescence in situ hybridisation (FISH) needed to be as small as possible.

The rapid acquisition of large numbers of 3D microscopic images of cells was pushed successfully, allowing medium- to high-throughput approaches. Protocols for automated classic and spinning disk confocal imaging were developed. Problems related to storage, automated quantitative analysis and interpretation of the large microscopy-based data sets were tackled and largely solved. An efficient image database was set up and computational methods developed to extract quantitative information from these data sets.

The 3DGENOME project revealed a number of 3D folding principles of the human genome inside the interphase cell nucleus and showed that folding rules are closely related to the arrangement of genes on the one-dimensional genome. Results of the programme constitute a solid base to start unravelling underlying molecular and physical mechanisms. In this sense, the 3DGENOME project has (literally) added a new dimension to genome research.

The impact on fundamental research in the field of the eukaryotic genome in general and the human genome in particular was considerable, as shown by the number of publications published up to present, based on results from this project in peer-reviewed international scientific journals: 49 publications. This number was expected to increase in the following years. In addition, 124 seminars about 3DGENOME-related work were presented at scientific conferences, workshops and research laboratories. This number, too, was expected to increase in the next years.

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