Every human cell packs two metres of DNA into a nucleus a few millionths of a metre across, and a protein called cohesin is the main architect of that folding. Researchers want to know exactly how cohesin builds the three-dimensional loops that bring distant genes and their control switches together, and how those loops change as a stem cell turns into a specialised cell like a neuron or a muscle fibre. The problem is that while scientists know cohesin is essential for this folding, they do not understand the precise molecular rules that determine which loops form, when, and why. This is fundamental science. The work will use new genetic tools to watch cohesin in action during real developmental transitions in mammalian cells, revealing the molecular choreography that underpins cell identity. If successful, it will provide a mechanistic framework for how genome topology collaborates with transcription factors to drive differentiation. There is no immediate medical or industrial application, but similar fundamental discoveries about chromosome organisation have already reshaped our understanding of developmental disorders and cancers where looping goes wrong.
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Spatial and temporal control of gene expression is essential for development of complex multicellular organisms. My research focuses on understanding fundamental mechanisms controlling gene expression in mammalian cells. We are investigating how cohesin-mediated three-dimensional chromosome architecture influences gene regulation which drives cell-specific gene programmes. Chromosome structure and function are intimately connected. Recent molecular methods have shed new light on our underst anding of chromosome topology and mechanisms which regulate gene activity. Recently, a modular organization of chromosomes has been discovered, embedding genes and regulatory elements into complex chromosomes in a simple way. This new layer of genome organization (termed chromosomal domains) provides a compelling framework whereby distal elements can interact to drive gene regulation. Cohesin is central to chromosomal topology. Cohesin exerts its effects on genes primarily by anchoring long -range chromatin loops. These loops are distributed throughout the genome, creating a network of long-range contacts which structure domains and also tether enhancers to promoters. The precise mechanisms by which specific cohesin sites are assembled and how this cohesin-based organization supports cell identity are not fully known, yet are fundamental to our understanding of gene regulation. We will deliver new mechanistic understanding of how cohesin-based genome organization influences gen e regulation. We will address the functional role and molecular determinants of cohesin-mediated structure during dynamic developmental transitions using powerful new genetic tools and systems. This work will lead to deeper insights of the molecular transitions which accompany normal lineage commitment and how topological configurations of chromatin collaborate with transcription factors to drive differentiation.
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