SKOV3 cells containing a truncated ARID1a protein have a restricted genome-wide response to glucocorticoids.

AT-rich interacting domain subunit 1a (ARID1a) is an essential SWI/SNF component frequently mutated in human cancers. ARID1a mutations have also been associated with glucocorticoid resistance, potentially related to the well-established role of the SWI/SNF complex in glucocorticoid target gene regulation. Glucocorticoids are steroid hormones important for regulating many physiological processes through the activation of the glucocorticoid receptor (GR). As GR interacts directly with ARID1a, we hypothesized that a truncating ARID mutation would interfere with GR-dependent gene regulation. Using high throughput RNA sequencing (RNA-SEQ) we show a restricted glucocorticoid response in SKOV3 cells, which contain an inactivating ARID1a mutation. We also show a lack of GR binding at the GR-dependent regulatory site in the Period 1 gene, which has previously been shown to require chromatin remodelling. Taken together, our data suggests that ARID1a may be required for regulation of a subset of glucocorticoid responsive genes. In the case of SKOV3 cells, in which ARID1a is mutated, glucocorticoid-dependent transcriptional regulation of these genes is significantly impaired.

Chromatin architecture and the regulation of nuclear receptor inducible transcription.

Epigenetic mechanisms alter the structure of local chromosome domains to dynamically regulate gene expression by signalling and propagating transcriptional states. Nuclear receptors, a stimulus-inducible class of transcription factors, interact with chromatin to regulate transcription. To promote transcription, nuclear receptors interact with genomic regulatory elements that are epigenetically marked by modified histone tails, DNA methylation status, histone variants, chromatin accessibility and long-range interactions. Advances in throughput have allowed the profiling of regulatory factor activity on a genome-wide scale, with recent evidence from genomic analyses highlighting novel aspects of DNA-binding factor actions on chromatin. In the present review, the current knowledge of the mechanisms regulating nuclear receptor occupancy at cis-regulatory elements is discussed, with particular emphasis on the glucocorticoid, oestrogen and androgen receptors. Epigenetic regulation of genomic elements direct cell-specific regulatory factor binding and contribute to human variation in factor occupancy. Through regulating nuclear receptor activity, the epigenome is a critical checkpoint in nuclear receptor induced gene expression in health and disease.