Cohesin is a protein complex best known for its role in chromosome biology, but recent work suggests additional functions in gene expression, development and cancer. Research in my lab uncovered a functional relationship between cohesin and the mammalian insulator protein CTCF (Cell 132: 422-433) and showed that cohesin forms long-range interactions between its binding sites (Nature 460: 410-413). Genetic deletion of the cohesin in developing thymocytes impaired the transcription and the rearran gement of the T cell receptor alpha chain locus (Nature 476: 467-471). Importantly, this work demonstrated that cohesin regulates gene expression independently of its canonical functions in the cell cycle. This realisation opened a new perspective on gene regulation, in line with growing awareness of the importance of higher order genome organisation. The aim of this proposal is to uncover the mechanisms by which cohesin regulates gene expression. 1) Can the structural and functional propert ies of cohesin required for gene regulation be separated from those for chromosome segregation? 2) What are the chromatin, transcriptional and long-range interaction landscapes that underlie cohesin-mediated gene regulation, and can they be used to derive experimentally testable models for cohesin function in interphase? 3) What factors control the expression, chromosomal loading and the function of cohesin in gene regulation, and can they be manipulated to reverse the effects of cohesin d epletion on gene expression? This work will provide a mechanistic understanding of how cohesin regulates gene expression and suggest approaches to the management of clinical conditions where cohesin function is compromised.