Drugging the 3D genome: strategies to combat cancers driven by cohesin deficiency

Host: Professor Ruth Arkell

Abstract

The cohesin complex plays key roles in the three-dimensional (3D) organisation of chromatin and is essential for cell division and gene expression.  Cohesin’s role in 3D genome organisation helps determine the accessibility of genes to transcriptional programmes downstream of signalling pathways. We and others have found that hundreds of genes are dysregulated upon cohesin deficiency, but it is not clear how this gene regulation could be ‘direct’.

Our results from human cancer cell lines and zebrafish models shows that minor gene expression changes in cohesin-deficient cells become dramatic in response to signalling pathways. Results from chromosome conformation experiments suggest that cohesin deficiency causes loss of constraints on 3D structure such that genes respond abnormally, transiently, when a signal is present. Transient inappropriate gene response is dampened by inhibition of enhancer function. We found that the Wnt signalling pathway is a druggable target in cohesin mutant cancers. Our current research is focusing on how properties of cohesin mutant cancer cells confer vulnerability to therapeutic strategies.

Biography

Professor Julia Horsfield is current Head of the Department of Pathology, Dunedin School of Medicine. She completed her PhD at the University of Otago in 1995. In 1996, she took up a Health Research Council of NZ Overseas Postdoctoral Fellowship to work at the University of Adelaide. There, she first became acquainted with control of the cell cycle in development, and took part in forward genetic screens for cell cycle regulators in Drosophila. Professor Horsfield then moved to the University of Auckland in late 1999, where she used a forward genetic screen to identify new leukaemia genes in zebrafish. This resulted in the identification of a cell cycle protein – cohesin. Lucky enough to have the opportunity to start her own lab at the University of Otago in 2007, she has spent the last 16 years trying to understand developmental and cancer roles for the cohesin complex. During this time, she created and directs the Otago Zebrafish Facility, and directed for the Genetics Otago research centre from 2017-2021.