In mammals, accurate regulation of gene expression relies on distal regulatory sequences such as enhancers. Enhancers are often located at large genomic distances from the genes that they control, and are thought to regulate transcription by physically associating with their target promoters. This in turn is linked to how chromosomes are folded in the three-dimensional space of the cell nucleus.
Our lab aims at understanding the fundamental principles underlying the interplay between chromosome structure and transcription. We are fascinated by fundamental questions that lay at the interface between molecular biology and physics.
Does chromosome structure control gene expression?
Several lines of evidence suggest that enhancers control gene expression by forming physical interactions with their target promtoers. However the fundamental principles of how interactions between regulatory sequences are translated into transcriptional outputs are unknown. We try to discover these principles using genomic engineering and experimental methods designed to quantitatively measure chromosome structure and transcription.
How dynamic is chromosome structure?
Current understanding of chromosome structure mostly relies on fixation-based techniques, which do not measure the dynamic properties of chromosome structure. Nothing is known on how often an enhancer encounters a promoter during a cell cycle, or how long their interactions last. It is also unknown if transcription occurs simultaneously with enhancer-promoter contacts, or if contacts are actually required to initiate transcription. We study these questions using live-cell microscopy approaches, and use polymer modeling to interpret the data.
Can we understand long-range transcriptional regulation quantitatively?
Our ambition is to discover the basic rules governing how regulatory sequences translate physical interactions into transcriptional outputs. All our experiments are designed to collect quantitative data, which can be interpreted and integrated using mathematical and physical models. We use a range of theoretical and computational tools, from bioinformatics to stochastic modeling and polymer physics.
Our toolset
Chromosome conformation capture methods
Live-cell imaging
Genome engineering
RNA and DNA FISH
Genomics and bioinformatics
Physical modeling
