Clinically, glucocorticoids are widely used as a treatment mainly due to their potent anti-inflammatory abilities, however these are associated with several side effects and furthermore some patients go on to develop glucocorticoid resistance. ARID1a mutations have been linked to glucocorticoid resistance and are frequently identified across numerous cancers; therefore it is important to determine the functional role of ARID1a to GR signalling. The ATPase driven SWItch/Sucrose NonFermentable (SWI/SNF) chromatin-remodelling complex interacts with GR through ARID1a. Chromatin-remodelling by the SWI/SNF complex is a vital component of genomic GR signalling, with chromatin being dynamically opened and closed at GR binding sites in target genes to regulate transcription. We therefore hypothesize ARID1a is key in facilitating this GR mediated transcriptional regulation. In this study expression profiling using next-generation RNA sequencing enables the assessment of GR regulated gene transcription in the absence of the full-length ARID1a and chromatin immunoprecipitation (ChIP) is used to assess GR and RNA Polymerase II binding. Here we assess ARID1a knock-down and the functional interference of the endogenous ARID1a by the overexpression of the ARID1a C-terminal in HeLa cells. Surprisingly, our genome-wide data shows that loss or functional interference of ARID1a does not impact upon the majority of robustly regulated GR responsive genes. In addition, our ChIP studies reveal no affect of ARID1a knock-down on GR or RNA Polymerase II binding at the Per1 gene, consisting of a chromatin-remodelling dependent GR binding site. Instead, we demonstrate the importance of GR regulation on cell-cycle progression through ARID1a and that disruption of this interaction impacts upon P53 pathways. We also reveal a novel role of GR in the regulation of histone gene expression. Understanding this role of GR is important for understanding the potential of GR as a therapeutic target in diseases associated with loss of ARID1a and those with cell-cycle dysregulation.
07 Nov 2016 - 09 Nov 2016