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4C technology: uncovering the multi-dimensional structure of the genome

Objective

The architecture of DNA in the cell nucleus is an emerging epigenetic key contributor to genome function. We recently developed 4C technology, a high-throughput technique that combines state-of-the-art 3C technology with tailored micro-arrays to uniquely allow for an unbiased genome-wide search for DNA loci that interact in the nuclear space. Based on 4C technology, we were the first to provide a comprehensive overview of long-range DNA contacts of selected loci. The data showed that active and inactive chromatin domains contact many distinct regions within and between chromosomes and genes switch long-range DNA contacts in relation to their expression status. 4C technology not only allows investigating the three-dimensional structure of DNA in the nucleus, it also accurately reconstructs at least 10 megabases of the one-dimensional chromosome sequence map around the target sequence. Changes in this physical map as a result of genomic rearrangements are therefore identified by 4C technology. We recently demonstrated that 4C detects deletions, balanced inversions and translocations in patient samples at a resolution (~7kb) that allowed immediate sequencing of the breakpoints. Excitingly, 4C technology therefore offers the first high-resolution genomic approach that can identify both balanced and unbalanced genomic rearrangements. 4C is expected to become an important tool in clinical diagnosis and prognosis. Key objectives of this proposal are: 1. Explore the functional significance of DNA folding in the nucleus by systematically applying 4C technology to differentially expressed gene loci. 2. Adapt 4C technology such that it allows for massive parallel analysis of DNA interactions between regulatory elements and gene promoters. This method would greatly facilitate the identification of functionally relevant DNA elements in the genome. 3. Develop 4C technology into a clinical diagnostic tool for the accurate detection of balanced and unbalanced rearrangements.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/chromosome
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

ERC-2007-StG
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Funding Scheme

ERC-SG - ERC Starting Grant
Leaflet | Map data © OpenStreetMap contributors, Credit: EC-GISCO, © EuroGeographics for the administrative boundaries

Host institution

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Address
Kloveniersburgwal 29 Het Trippenhuis
1011 JV Amsterdam
Netherlands
Activity type
Other
EU contribution
€ 1 225 000
Principal investigator
Wouter Leonard De Laat (Dr.)
Administrative Contact
Don Van Velzen (Mr.)

Beneficiaries (1)

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands
EU contribution
€ 1 225 000
Address
Kloveniersburgwal 29 Het Trippenhuis
1011 JV Amsterdam
Activity type
Other
Principal investigator
Wouter Leonard De Laat (Dr.)
Administrative Contact
Don Van Velzen (Mr.)