Poster Presentation 45th Lorne Genome Conference 2024

Transient enhancer-promoter interactions precede transcription of androgen-induced genes upon DHT treatment in prostate cancer cells (#257)

Elyssa M Campbell 1 2 , Grady Smith 2 , Geraldine Laven-Law 3 , Yolanda Colino Sanguino 1 4 , David Moulder 2 , Qian Du 1 2 , Amanda Khoury 1 2 , Katherine A Giles 5 , Theresa A Hickey 3 , Fatima Valdes Mora 1 2 4 , Susan J Clark 1 2 6 , Joanna Achinger-Kawecka 1 2 6
  1. St Vincent's Clinical School, UNSW, Sydney, NSW, Australia
  2. Garvan Institute of Medical Research, Sydney, NSW, Australia
  3. Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
  4. Children's Cancer Institute, Sydney, NSW, Australia
  5. Children's Medical Research Institute, Westmead, NSW, Australia
  6. *Authors 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 combined chromatin conformation capture (Hi-C and Promoter Capture Hi-C) with the profiling of transcription factor binding, histone modifications (CUT&RUN) and transcription (RNA-seq and TT-seq) during a finely resolved time-course of DHT treatment in prostate cancer cells (control, 5min, 10min, 20min, 30min, 2hrs, 4hrs and 16hrs). We found that chromatin remodelling, AR and FOXA1 binding at interacting promoters were transiently present at the earliest time-points, while androgen-induced gene activation and AR binding at distal regulatory elements occurred mostly at later time-points. Our results demonstrate that dynamic changes in AR-driven 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.

  1. Debes JD, Tindall DJ. Mechanisms of Androgen-Refractory Prostate Cancer. New England Journal of Medicine 2004; 351: 1488-1490.
  2. Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. New England Journal of Medicine 2013; 368: 1314-1325.
  3. Pomerantz MM, Li F, Takeda DY, Lenci R, Chonkar A, Chabot M et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nature Genetics 2015; 47: 1346-1351.
  4. Pomerantz MM, Qiu X, Zhu Y, Takeda DY, Pan W, Baca SC et al. Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nature Genetics 2020; 52: 790-799.
  5. Heinlein CA, Chang C. Androgen Receptor in Prostate Cancer. Endocrine Reviews 2004; 25: 276-308.
  6. Zhao SG, Chen WS, Li H, Foye A, Zhang M, Sjöström M et al. The DNA methylation landscape of advanced prostate cancer. Nature Genetics 2020; 52: 778-789.