Project description DEENESFRITPL The sequences that drive LAD formation Lamina-associated domains (LADs) cover 40 % of the human genome and hold thousands of transcriptionally repressed genes. While LAD recognition and anchoring to the nuclear lamina (NL) need to be tightly regulated to ensure acute gene expression, little is known about the underlying mechanisms. LADs are known to be A and T nucleotide-rich but other sequence determinants are poorly characterised. The EU-funded I.am.a.LAD project will first examine how LAD recognition is linked to their A/T content. Second, through this Marie Skłodowska-Curie fellowship, the researcher will develop a tool to search for additional sequence determinants. Finally, the MSCA fellow will identify sequences that drive LAD formation and elucidate the role of the cohesin complex in this process. Show the project objective Hide the project objective Objective "Lamina-associated domains (LADs) are large chromatin domains anchored to a protein meshwork coating the inner nuclear envelope, the nuclear lamina (NL). They cover 40% of the human genome and hold thousands of transcriptionally repressed genes. While some LADs can be locally detached from the NL upon gene activation, others are constitutively at the NL. This implies that LAD recognition and anchoring to the NL has to be tightly regulated to ensure acute gene expression. However, little is known about mechanisms governing LAD recognition and targeting to the NL. LADs are known to be A and T nucleotide-rich, but other sequence determinants have remained poorly characterized so far. In this project I will (1) investigate whether LAD recognition is directly linked to their high A/T content and (2) develop a novel tool to search for additional sequence determinants. First, I will insert in the mouse genome long DNA stretches of varying A/T percentages and determine whether A/T-rich sequences preferentially associate with the NL. Second, I will develop an approach to randomly scramble a LAD sequence organization. This method relies on the recombination between LoxP sites randomly inserted by local ""hopping"" of a transposable element. After determining the effects of the resulting rearrangements on NL association and expression of the surrounding genes, I will identify sequences that drive LAD formation. Besides, the cohesin complex partitions the genome into topologically associated domains and hence has a major impact in genome 3D folding. At last, I will investigate cohesin’s role in LAD formation and remodeling after recombination. Altogether, this project will result in an unprecedented characterization of LAD biology, a deeper understanding of cohesin’s role in genome folding and set up a novel genome-scrambling technique with large applications in genome biology." Fields of science engineering and technologymaterials engineeringfibersnatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsengineering and technologymaterials engineeringcoating and filmsnatural sciencesbiological sciencesgeneticsgenomes Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2020 - Individual Fellowships Call for proposal H2020-MSCA-IF-2020 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS Net EU contribution € 175 572,48 Address Plesmanlaan 121 1066 CX Amsterdam Netherlands See on map Region West-Nederland Noord-Holland Groot-Amsterdam Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
