Mechanism of action of the tumour suppressor ARID1A

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Human BAF complexes are a series of multi-subunit assemblies that act to reconfigure chromatin. They are conserved across eukaryotes and were first identified in yeast where they were named SWI/SNF complexes and found to act to enable gene expression by regulating chromatin accessibility. In mammals, the predominant BAF complex acts mainly at enhancers where it generates accessible chromatin. The ARID1A subunit of this complex is mutated in approximately 50% of endometrial and ovarian clear cell cancers, but at background levels in tumours of other tissues such as Glioblastoma. Despite these prominent associations, the mechanistic basis for this tissue specificity is poorly understood.  

To gain insight into the mechanisms by which ARID1A reprogrammes cells, we have engineered cell lines to allow acute degradation of ARID1A. This enables us to track epigenetic and transcriptional changes over time. In this project we aim to reveal the pathway(s) by which loss of ARID1A promotes cancer. In this project changes to the distribution of transcription factors, histone modifications and changes to chromatin structures will be monitored to characterise the rapid changes driven by loss of ARID1A. This will involve the use of techniques such as chromatin immunoprecipitation ATAC-seq and nuc-seq. We will also monitor transcription using single cell RNA seq. We will integrate this data to discover gene regulatory networks triggered by loss of ARID1A. We will perform these experiments in cells of different tissue types to gain insight into why action of BAF complexes is tissue specific. This project will provide a deeper understanding into how ARID1A affects chromatin structure and transcription in different tissues.  

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