Decoding the epigenetics and chromatin loop dynamics of androgen receptor-mediated transcription

Umut Berkay Altıntaş, Ji-Heui Seo, Claudia Giambartolomei, Dogancan Ozturan, Brad J. Fortunato, Geoffrey M. Nelson, Seth R. Goldman, Karen Adelman, Faraz Hach, Matthew L. Freedman and Nathan A. Lack ()
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Umut Berkay Altıntaş: University of British Columbia
Ji-Heui Seo: Dana-Farber Cancer Institute
Claudia Giambartolomei: Human Technopole
Dogancan Ozturan: University of British Columbia
Brad J. Fortunato: Dana-Farber Cancer Institute
Geoffrey M. Nelson: Harvard Medical School
Seth R. Goldman: Harvard Medical School
Karen Adelman: Harvard Medical School
Faraz Hach: University of British Columbia
Matthew L. Freedman: Dana-Farber Cancer Institute
Nathan A. Lack: University of British Columbia

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Androgen receptor (AR)-mediated transcription plays a critical role in 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 investigate the AR-driven epigenetic and chromosomal chromatin looping changes by generating 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 find that AR binding induces sequential changes in the epigenetic features at CREs, independent of gene expression. Further, we show 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 propose and experimentally validate 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 insights into AR-mediated gene expression upon acute androgen simulation and develop a mechanistic framework to investigate nuclear receptor mediated perturbations.

Date: 2024
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DOI: 10.1038/s41467-024-53758-5

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