Epigenetic disruption of the RARγ complex impairs its function to bookmark AR enhancer interactions required for
Sajad A Wani1, Shahid Hussain2,3, Jaimie S Gray1
1Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH 43210.
Abstract:
The current study in prostate cancer (PCa) focused on the genomic mechanisms at the cross-roads of pro-differentiation signals and the emergence of lineage plasticity. We explored an understudied cistromic mechanism involving RARγ's ability to govern AR cistrome-transcriptome relationships, including those associated with more aggressive PCa features. The RARγ complex in PCa cell models was enriched for canonical cofactors, as well as proteins involved in RNA processing and bookmarking. Identifying the repertoire of miR-96 bound and regulated gene targets, including those recognition elements marked by m6A, revealed their significant enrichment in the RARγ complex. RARγ significantly enhanced the AR cistrome, particularly in active enhancers and super-enhancers, and overlapped with the binding of bookmarking factors. Furthermore, RARγ expression led to nucleosome-free chromatin enriched with H3K27ac, and significantly enhanced the AR cistrome in G2/M cells. RARγ functions also antagonized the transcriptional actions of the lineage master regulator ONECUT2. Similarly, gene programs regulated by either miR-96 or antagonized by RARγ were enriched in alternative lineages and more aggressive PCa phenotypes. Together these findings reveal an under-investigated role for RARγ, modulated by miR-96, to bookmark enhancer sites during mitosis. These sites are required by the AR to promote transcriptional competence, and emphasize luminal differentiation, while antagonizing ONECUT2.
Insights
This study reveals how retinoic acid receptor gamma (RARγ), modulated by miR-96, bookmarks enhancers in prostate cancer (PCa) cells. This mechanism influences Androgen Receptor (AR) activity and promotes differentiation, impacting aggressive PCa phenotypes.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Prostate cancer (PCa) progression involves complex genomic mechanisms and lineage plasticity.
- The role of retinoic acid receptor gamma (RARγ) in governing Androgen Receptor (AR) cistrome-transcriptome relationships remains understudied.
- Understanding these mechanisms is crucial for identifying therapeutic targets in aggressive PCa.
Approach:
- Investigated RARγ's cistromic function in PCa cell models.
- Analyzed RARγ complex composition, including cofactors and RNA processing proteins.
- Identified miR-96 bound and regulated gene targets, including m6A-marked elements.
- Examined RARγ's impact on AR cistrome, chromatin accessibility (H3K27ac), and cell cycle (G2/M).
- Assessed the antagonism between RARγ and the lineage regulator ONECUT2.
Key Points:
- RARγ complex is enriched with RNA processing and bookmarking factors.
- RARγ enhances the AR cistrome at active enhancers and super-enhancers, overlapping with bookmarking factors.
- RARγ promotes nucleosome-free chromatin and enhances the AR cistrome in G2/M cells.
- RARγ antagonizes the transcriptional activity of ONECUT2.
- Gene programs regulated by miR-96 or antagonized by RARγ are linked to alternative lineages and aggressive PCa.
Conclusions:
- RARγ, modulated by miR-96, bookmarks enhancer sites during mitosis.
- These RARγ-bookmarked sites are essential for AR-mediated transcriptional competence and luminal differentiation.
- RARγ's function antagonizes ONECUT2, influencing lineage plasticity and aggressive PCa phenotypes.
- This study uncovers a novel role for RARγ in regulating prostate cancer cell fate and progression.
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