Decoding the Epigenetics and Chromatin Loop Dynamics of Androgen Receptor-Mediated Transcription

TL;DR

This study explores how androgen receptor binding influences gene expression through epigenetic and chromatin loop changes in prostate cells.

Contribution

The paper introduces an unbalanced multi-enhancer model explaining how AR-bound enhancers differentially impact gene expression.

Findings

AR binding induces sequential epigenetic changes at CREs without immediate gene expression changes.

AR increases contact frequency of pre-existing chromatin loops rather than creating new ones.

Gene expression correlates strongly with the contact frequency of enhancer-promoter interactions.

Abstract

Androgen receptor (AR)-mediated transcription plays a critical role in normal prostate development and prostate cancer growth. AR drives gene expression by binding to thousands of cis-regulatory elements (CRE) that loop to hundreds of target promoters. With multiple CREs interacting with a single promoter, it remains unclear how individual AR bound CREs contribute to gene expression. To characterize the involvement of these CREs, we investigated the AR-driven epigenetic and chromosomal chromatin looping changes. We collected a kinetic multi-omic dataset comprised of steady-state mRNA, chromatin accessibility, transcription factor binding, histone modifications, chromatin looping, and nascent RNA. Using an integrated regulatory network, we found that AR binding induces sequential changes in the epigenetic features at CREs, independent of gene expression. Further, we showed that binding of AR does not result in a substantial rewiring of chromatin loops, but instead increases the contact frequency of pre-existing loops to target promoters. Our results show that gene expression strongly correlates to the changes in contact frequency. We then proposed and experimentally validated an unbalanced multi-enhancer model where the impact on gene expression of AR-bound enhancers is heterogeneous, and is proportional to their contact frequency with target gene promoters. Overall, these findings provide new insight into AR-mediated gene expression upon acute androgen simulation and develop a mechanistic framework to investigate nuclear receptor mediated perturbations.