A protein complex called cohesin, best known for holding chromosomes together during cell division, also switches genes on and off—and scientists want to know how. This matters because when cohesin goes wrong, it disrupts gene expression in ways linked to developmental disorders and cancers. The researchers have already shown that cohesin controls gene activity independently of its cell-division role, and that it helps form long-range loops of DNA that bring distant regulatory elements together. But the precise mechanism remains unknown. This project asks three concrete questions: whether cohesin’s gene-regulatory function can be separated from its chromosome-segregation job; what the full landscape of DNA loops, chromatin changes, and transcription looks like when cohesin is at work; and which factors control cohesin’s loading onto DNA and its effects on gene expression. This is fundamental science. There is no immediate clinical application. But understanding how a single protein complex orchestrates genome organisation could eventually point toward ways to reverse the gene-expression defects seen in cohesin-related diseases—much as basic discoveries about DNA looping and insulator proteins have reshaped how researchers think about gene regulation across biology.
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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.
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