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. Unconstrained 3D chromatin structure may not be the whole picture, because we recently found that the Wnt effector protein, beta-catenin, is stabilised in cohesin mutant cells. This raises the possibility that signalling pathways and cohesin mutation compound to abnormally regulate gene expression at multiple levels. Overall, these results have relevance to the interpretation of “cohesinopathy” human developmental syndromes, and a range of cancers, that are caused by mutations in the cohesin complex or its regulators.