4DG - Dynamic structural models of the 4D genome
Cell fate decisions are programmed at several levels of regulation of gene expression. One such level involves so-called epigenetic modifications of chromatin, an assembly of DNA and histones. Dynamic interactions between chromosomes in the 3-dimensional (3D) space of the cell nucleus also affect gene expression. This suggests that 3D genome conformation is regulated during development, that is, in a 4D space where the fourth component is time. Nutrients also seem to modulate epigenetic states, adding complexity to the regulation of gene expression. We aim to establish a mechanistic connection between 3D genome conformation, gene expression patterns and cellular metabolic state. We will test three hypotheses. The first is that lineage-specific differentiation shapes developmental transitions in the 3D chromatin landscape. This will be tested by generating novel 3D chromatin models from chromosome-chromosome and chromosome-nuclear envelope interaction data and modeling their transitions during adipogenic and neurogenic differentiation. The second is that 4D chromatin conformation predicts gene expression patterns. We will use Bayesian techniques to learn which aspects of 3D chromatin conformation or changes therein predict gene expression changes during differentiation. The third is that the 4D genome is influenced by cellular metabolism via a nutrient-sensing histone modification. This will be tested by subjecting cells to glucose stress, and monitoring how the 3D genome is affected and whether changes are mediated by H2B GlcNAcylation a glucose-sensing modification which pre-patterns the association of nuclear lamins with chromatin (and hence the radial positioning of loci). This transdisciplinary project combines stem cell biology, chromatin biology and metabolic studies with high-throughput genomics, statistical modeling and software development. It is designed for 1 postdoc and 2 PhD students with technical assistance.
- Begrunnelse: Ikke sensitive data
- Lagret: Room 2268
- Biobanknummer: 2013/2102
- Ansvarlig: Philippe Collas
REK - Ja 1 fil
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