Oral Presentation Australian Epigenetics Alliance Conference 2022

Transient enhancer-promoter interactions precede transcription of androgen-induced genes upon DHT treatment in prostate cancer cells (#6)

Elyssa M Campbell 1 2 , Grady C Smith 2 , Geraldine Laven-Law 3 , Yolanda Colino Sanguino 1 4 , David Moulder 2 , Qian Du 1 2 , Amanda Khoury 2 , Katherine A Giles 5 , Theresa A Hickey 3 , Fatima Valdes Mora 1 4 , Joanna Achinger-Kawecka 1 2 6 , Susan J Clark 1 2 6
  1. Faculty of Medicine, St Vincent's Clinical School, UNSW, Sydney, NSW, Australia
  2. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, SA, Australia
  4. Cancer Epigenetic Biology and Therapeutics, Children’s Cancer Institute, Sydney, NSW, Australia
  5. Children's Medical Research Institute, Sydney, NSW, Australia
  6. Contributed Equally, *

Androgen receptor (AR)-mediated transcription is the primary driver of prostate cancer growth and proliferation [1, 2]. Androgen treatment induces AR binding to the DNA primarily at regulatory enhancer elements, resulting in rapid changes to transcriptional profiles [3-6]. However, the precise relationship between androgen-induced gene expression changes and AR-enhancer binding has not been characterized in the context of 3D chromatin interactions and therefore a high-resolution view of the temporal dynamics of androgen-induced gene activation is still missing.

To determine the molecular order of events associated with transcription of androgen-induced genes, we performed Hi-C, Promoter Capture Hi-C (PCHi-C), RNA-Seq and AR ChIP-Seq experiments in DHT treated prostate cancer cell lines at five time-points (control, 30min, 2hrs, 4hrs and 16hrs) and integrated the temporal data sets. We found that while androgen-induced gene activation and AR binding occurred mostly at later time-points (4hrs and 16hrs post-DHT), the majority of differential promoter-enhancer interactions were transiently present at the earliest time-point of 30mins post-DHT. At 16hrs more than half of these interactions were subsequently lost. Our results demonstrate that changes in AR-enhancer-promoter interactions precede gene activation and unexpectedly high levels of gene transcription were associated with loss of these interactions. Our findings are consistent with the conclusion that enhancer-promoter interactions transiently activate gene expression, thereby uncoupling the temporal dynamics of chromatin interactions from those of transcription.

 This novel dataset provides a temporally resolved map of androgen-induced chromatin and transcription changes in prostate cancer, revealing potential causal relationships between 3D chromatin structure, AR binding at enhancers, and gene activation.

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