Structure vs. Function: Chromosome architecture and the regulation of gene expression

Accurate regulation of gene expression is fundamental for the correct development of tissues in all living organisms. In mammals, control of gene expression relies critically on DNA sequences named enhancers, which are often located at very large genomic distances from the gene that they control. How such distant regulatory sequences act specifically on one or a limited number of genes, despite the large intervening stretches of non-coding genomic DNA is unknown. Emerging evidence suggests that the three-dimensional structure and dynamics of chromosomes inside cell nuclei plays a key role in the communications between enhancers and their target genes. However, the precise mechanism that link chromosome conformation to gene regulation remain largely unknown. What is the exact structure of the chromatin fiber within chromosomes? Which proteins control it and how? How does chromosome structure vary from cell to cell and in time? What are the biophysical principles by which chromosome folding determine the activity of enhancers? Addressing these questions requires to quantitatively measure gene expression and chromosome conformation, including their cell-to-cell and temporal variability, and to interpret the data using physical models. Research in our lab uses genomic engineering, molecular biology experiments designed to provide quantitative data, single-cell assays and physical models to understand the mechanisms by which three-dimensional chromosome structure and dynamics control transcriptional regulation by enhancers.