ARID1A supports the expression of YAP target genes by facilitating the binding of TEAD on enhancers in epithelial breast cells

YAP plays a significant role as an oncogenic driver in a multitude of tumour types. In the majority of cases, its hyperactivity is not associated with any genomic abnormalities. Consequently, it can be reasonably suggested that the aberrant activity of YAP in cancer should be sought in epigenetic dysregulation. Although YAP lacks a DNA binding domain, it acts as a positive regulator of the transcription of a large set of target genes in conjunction with the DNA binding proteins of the TEAD family. Conversely, ARID1A, which is a key component of the SWI/SNF chromatin remodelling complex, is primarily regarded as a tumour suppressor gene, whose activity is inactivated by recurrent mutations in numerous cancer types. ARID1A is in fact necessary to support expression of genes involved in DNA damage response, cell growth control and several other processes. To date, numerous studies have demonstrated a functional interplay between these two factors in both physiological processes and oncogenesis. Nevertheless, no unified mechanistic model has been established, and instead, a context-dependent interplay has been observed. The present PhD project offers a novel account of the complex interplay between ARID1A and YAP activity in breast epithelial cells under high mechanical cues. The analysis of available ATAC-seq data from cancer cell lines revealed that the loss of ARID1A resulted in a slight global reduction in chromatin accessibility, which was predominantly observed at enhancer regions. An analysis of transcription factor motifs in the less accessible enhancers revealed that TEAD was among the top most enriched. Finally, cross-referencing ATAC-seq data with ChIP-seq for TEAD revealed that the loss of ARID1A in these TEAD-bound enhancers resulted in a pronounced reduction in accessibility. Our data on gene expression and GO term analysis direct us on a model in which ARID1A loss is detrimental for YAP-dependent biological processes like proliferation and migration in cells immortalised but non tumorigenic. Finally, we took advantage of ARID1A Knock Out clone to gain insights into the mechanism through which it regulates YAP dependent gene expression. Our data show that ARID1A enables TEAD-4 binding to the promoters of its main target gene CTGF. Taken together all this evidence supports a model in which ARID1A supports TEAD binding and therefore represents a prerequisite to support YAP transcriptional programme in cells experiencing high mechanical stress. This model is in agreement with previous observations suggesting that ARID1A is required in the early phases of tumorigenesis, while its loss confers a competitive advantage to cells in later stages of tumour progression. Further experimentation will be necessary to validate this model and to elucidate the effects of concomitant hyperactivation of YAP and loss of ARID1A in in vitro and in vivo models of cancer progression.