OR06-05 Differential Regulation Of Transcriptional State Switching Revealed By Endocrine Disruptor Chemicals

Abstract

Abstract Disclosure: C. Day: None. P. Yasar: None. J. Rodriguez: None. Gene regulation is complex, involving the coordination of hundreds of proteins that function to control genome accessibility, mediate enhancer-promoter interactions, and initiate transcription. At individual loci, transcriptional initiation is stochastic in time, resulting in short periods of nascent RNA synthesis known as transcriptional bursts. Some genes switch between periods of transcriptional bursting and long periods of inactivity. These variable periods of inactivity can last days and lead to gene expression heterogeneity in cancer cells. Here we investigate how transcriptional bursting of estrogen regulated genes is modulated by low affinity estrogen receptor alpha (ERα) ligands, specifically endocrine disruptor chemicals (EDCs). Using live cell MS2-imaging of the estrogen responsive TFF1 gene, we observed that cells treated with genistein or Bisphenol A (BPA) exhibited burst initiation and duration kinetics which were indistinguishable from cells induced with Estradiol (E2). However, there was a 50% reduction in the number of active alleles in BPA treated cells. Our data suggest that BPA treated cells can activate TFF1 alleles that are in transcriptionally permissive states, while E2 and genistein can additionally switch alleles from a repressed state to a transcriptionally permissive state. To understand the contribution of the enhancer on state switching, we deleted the nearby enhancer and observed a similar number of active alleles between cells treated with E2 or BPA. Taken together, our work reveals that ERα and the TFF1 enhancer have roles in activation and state switching at a heterogeneously expressed gene. Our results also highlight different modes of regulation for endocrine disruptor chemicals at the same gene. Presentation: Thursday, June 15, 2023