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Functional mapping of androgen receptor enhancer activity.

Chia-Chi Flora Huang¹, Shreyas Lingadahalli¹, Tunc Morova¹

¹Vancouver Prostate Centre, Department of Urologic Science, University of British Columbia, Vancouver, Canada.

|May 12, 2021

Summary

Androgen receptor (AR) binding sites in prostate cancer are mostly inactive. Functional mapping reveals AR-regulated enhancers are crucial hubs for gene transcription and interactions.

Keywords:

Androgen receptor Enhancers Non-coding mutations Prostate cancer STARRseq

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Area of Science:

Molecular Biology
Genomics
Cancer Research

Background:

Androgen receptor (AR) plays a key role in prostate cancer development and progression.
Activated AR binds to DNA cis-regulatory elements to drive gene expression.
A significant excess of AR binding sites exists compared to differentially expressed genes, with their regulatory role unclear.

Purpose of the Study:

To elucidate the regulatory mechanisms of AR-mediated transcription.
To functionally characterize AR binding sites and their enhancer activity.
To understand how excess AR binding sites influence gene transcription.

Main Methods:

Generated a locus-specific map of enhancer activity for AR binding sites.
Utilized Self-Transcribing Active Regulatory Regions sequencing (STARRseq) for functional testing.
Correlated enhancer annotations with in vitro cell lines and clinical prostate cancer samples.

Main Results:

Only 7% of AR binding sites exhibited androgen-dependent enhancer activity.
The majority of AR binding sites were inactive or constitutively active enhancers.
AR-regulated enhancers form chromosomal loops with promoters, essential for transcription.
Somatic mutations in these enhancers can affect their activity.

Conclusions:

AR-regulated enhancers function as regulatory hubs.
These hubs enhance interactions between AR binding sites and gene promoters.
A functional map of AR enhancer activity provides insights into prostate cancer gene regulation.