Epigenetic changes arising from acute depletion of the tumour suppressor ARID1A

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• Tom Owen-Hughes, University of Dundee
• Tuesday 29 November 2022, 12:30-13:30
• Lecture Theatre, Department of Pathology, Tennis Court Road.

If you have a question about this talk, please contact Michael Boemo.

The ARID1A subunit of SWI /SNF chromatin remodelling complexes is a potent tumour suppressor. It is a major driver for ovarian clear cell carcinoma and endometrial cancer. Like many genes involved in signalling, the relationship between mutations to the gene and the phenotype is complexes. We have attempted to address this using an auxin degron to trigger acute depletion of ARID1A . Loss of chromatin accessibility is detected at thousands of loci within a couple of hours. At these sites ARID1A containing complexes act to generate accessible minidomains of nucleosomes. ARID1A also interacts with the co-activator EP300 . When ARID1A is degraded EP300 dissociates from many locations. The locations where both ARID1A dissociates and chromatin accessibility is lost are strongly associated with downregulated transcription. In contrast, sites of gained EP300 occupancy are linked to genes that are transcriptionally upregulated. These chromatin changes are associated with a small number of genes that are differentially expressed in the first hours following loss of ARID1A . Indirect or adaptive changes dominate the transcriptome following growth for days after loss of ARID1A and result in strong engagement with cancer pathways. The identification of this hierarchy suggests that upstream steps may represent new sites for intervention in ARID1A -driven diseases. This may be generally applicable for cancers driven by alterations to epigenetic regulators.

This talk is part of the Cellular and Molecular Pathology Seminars series.

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• Cellular and Molecular Pathology Seminars
• Lecture Theatre, Department of Pathology, Tennis Court Road

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