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SUMMARY:Epigenetic changes arising from acute depletion of the tumour supp
 ressor ARID1A - Tom Owen-Hughes\, University of Dundee
DTSTART:20221129T123000Z
DTEND:20221129T133000Z
UID:TALK183911@talks.cam.ac.uk
CONTACT:Michael Boemo
DESCRIPTION: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 comp
 lexes. 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 containi
 ng 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 dissocia
 tes and chromatin accessibility is lost are strongly associated with downr
 egulated transcription.  In contrast\, sites of gained EP300 occupancy are
  linked to genes that are transcriptionally upregulated. These chromatin c
 hanges are associated with a small number of genes that are differentially
  expressed in the first hours following loss of ARID1A. Indirect or adapti
 ve changes dominate the transcriptome following growth for days after loss
  of ARID1A and result in strong engagement with cancer pathways. The ident
 ification of this hierarchy suggests that upstream steps may represent new
  sites for intervention in ARID1A-driven diseases. This may be generally a
 pplicable for cancers driven by alterations to epigenetic regulators.
LOCATION:Lecture Theatre\, Department of Pathology\, Tennis Court Road
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