Effects of Concentration, Timing, and Pattern of Hormone Stimulation on Gene Regulation in vivo Mediated by Estrogen Receptors

Authors

• ST Ellison
• K Derr
• PJ Derr
• J Zhu
• M Ferrer

Abstract

Previous studies have established a strong relationship between circadian rhythms and endocrine homeostasis. However, the secretion of many hormones follows both circadian and ultradian patterns. Utilizing the glucocorticoid receptor (GR) as a model system, the impacts of the stimulation patterns of hormones on GR dynamics and downstream gene regulation have been thoroughly examined (Flynn et al. (2018), Stavreva et al. (2019), Stafford et al. (2020)).

Building upon the existing knowledge of GR, we employ techniques, including genomics, single molecule tracking (SMT), and high throughput microscopy, to investigate the effects of ultradian and constant hormone stimulation on the mobility of the estrogen receptor (ER) and regulation of ER target genes. We have successfully tagged endogenous ER in MCF7 cells, allowing us to study the spatiotemporal dynamics of ER under estrogen (E2) treatment. Furthermore, we visualized RNA synthesis at both the single-cell and single-promoter levels by using a previously established cell line with 24xMS2 repeats integrated into the 3’ UTR of the ER-responsive TFF1gene.

Our data revealed that in contrast to GR, E2 hormone fluctuations have much weaker impacts on ER dynamics and no effect on ER-mediated gene responses. This is likely due to the strong ER affinity to E2 and the preservation of the ER-E2 complex even after the depletion of E2 from the growth media. Understanding ER dynamics and its role in gene regulation has the potential to aid in the development of advanced treatment strategies targeting cancers that arise from the dysregulation of ER.

Scientific Focus Area: Cell Biology

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