Androgen Receptor-Mediated Transcription Regulation under Pulsatile and Constant Hormone Stimulation

Authors

• HK LaPoint
• DA Stavreva
• K Wagh
• LM Hoang
• A Upadhyaya
• RL Schiltz
• R Chari
• GL Hager

Abstract

Previous studies have established a strong relationship between circadian rhythms and endocrine homeostasis. The secretion of many hormones follows an ultradian/pulsatile (under 24h) pattern. The glucocorticoid receptor (GR) was our model system, because the hormone stimulation effects on dynamics, gene regulation, and metabolic and cognitive health have been thoroughly examined(Stavreva et al., 2009, 2016, and 2019; Flynn et al., 2018; Lightman et al., 2020; Kalafatakis et al., 2021). Building upon this knowledge, we employed genomics, single-molecule tracking (SMT), and high-throughput microscopy, to investigate the effects of ultradian and constant testosterone stimulation on androgen receptor (AR) mobility and the regulation of AR-regulated genes. Tagging endogenous AR allows us to measure dwell times and bound fraction change under different hormone stimulations via SMT. ChIP- and RNA-seq is used to map changes in AR binding genome-wide and to the transcriptome, respectively. Preliminary data indicate that low levels of testosterone (under 1nM) can fully activate AR, resulting in an increase in bound fraction and gene response. This suggests that the levels (often ≥10nM) used in many AR studies are far higher than physiological levels. Hormone washout has a weaker effect on AR than GR, suggesting that AR-ligand interactions are stronger than those between GR/natural glucocorticoids.

Uncovering AR dynamics and gene regulation in response to ultradian testosterone secretion will improve our understanding of AR signaling and inform the development and use of advanced treatment strategies such as hormone replacement therapy and targeted treatments against diseases arising from dysregulation of AR signaling, such as prostate cancer.

Scientific Focus Area: Molecular Biology and Biochemistry

This page was last updated on Tuesday, August 6, 2024