Altered cofactor recruitment and nucleosome dynamics underlie bisphenol A's impact on ERα-mediated transcriptional bursting.

Transcription initiation at hormone-responsive gene promoters involves recruitment of numerous proteins that initiate stochastic events known as transcriptional bursts. Estrogen responsive genes are regulated by Estradiol (E2) that binds to the Estrogen Receptor-α (ERα), allowing ERα to interact with DNA regulatory elements, recruit cofactors, and initiate transcription. Here, we utilized single-molecule imaging to determine how ERα mediated transcription is altered by non-canonical ligands such as Bisphenol A (BPA). Our analysis showed that the gene exhibited similar burst initiation kinetics in BPA-treated cells compared to cells treated with E2. However, there was a significant reduction in the number of active alleles in the BPA-treated cells. We show that while BPA bound ERα did induce chromatin remodeling, nucleosome positioning was altered and coincided with reduced transcription factor binding. Additionally, BPA treatment impaired enhancer mediated bursting. Together, this demonstrates that BPA disrupts transcriptional states by altering gene specific ERα cofactor recruitment.