HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers
- PMID: 37638746
- PMCID: PMC10602887
- DOI: 10.1093/nar/gkad700
HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers
Abstract
Incorporation of histone variant H3.3 comprises active territories of chromatin. Exploring the function of H3.3 in prostate cancer (PC), we found that knockout (KO) of H3.3 chaperone HIRA suppresses PC growth in vitro and in xenograft settings, deregulates androgen-induced gene expression and alters androgen receptor (AR) binding within enhancers of target genes. H3.3 affects transcription in multiple ways, including activation of p300 by phosphorylated H3.3 at Ser-31 (H3.3S31Ph), which results in H3K27 acetylation (H3K27Ac) at enhancers. In turn, H3K27Ac recruits bromodomain protein BRD4 for enhancer-promoter interaction and transcription activation. We observed that HIRA KO reduces H3.3 incorporation, diminishes H3.3S31Ph and H3K27Ac, modifies recruitment of BRD4. These results suggest that H3.3-enriched enhancer chromatin serves as a platform for H3K27Ac-mediated BRD4 recruitment, which interacts with and retains AR at enhancers, resulting in transcription reprogramming. In addition, HIRA KO deregulates glucocorticoid- (GR) driven transcription of genes co-regulated by AR and GR, suggesting a common H3.3/HIRA-dependent mechanism of nuclear receptors function. Expression of HIRA complex proteins is increased in PC compared with normal prostate tissue, especially in high-risk PC groups, and is associated with a negative prognosis. Collectively, our results demonstrate function of HIRA-dependent H3.3 pathway in regulation of nuclear receptors activity.
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
Figures
![Graphical Abstract](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700figgra1.gif)
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig1.gif)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig2.gif)
![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig3.gif)
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig4.gif)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig5.gif)
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig6.gif)
![Figure 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig7.gif)
![Figure 8.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig8.gif)
![Figure 9.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig9.gif)
![Figure 10.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig10.gif)
![Figure 11.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig11.gif)
![Figure 12.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10602887/bin/gkad700fig12.gif)
Update of
-
HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers.bioRxiv [Preprint]. 2023 May 8:2023.05.08.536256. doi: 10.1101/2023.05.08.536256. bioRxiv. 2023. Update in: Nucleic Acids Res. 2023 Oct 27;51(19):10194-10217. doi: 10.1093/nar/gkad700. PMID: 37214820 Free PMC article. Updated. Preprint.
Similar articles
-
HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers.bioRxiv [Preprint]. 2023 May 8:2023.05.08.536256. doi: 10.1101/2023.05.08.536256. bioRxiv. 2023. Update in: Nucleic Acids Res. 2023 Oct 27;51(19):10194-10217. doi: 10.1093/nar/gkad700. PMID: 37214820 Free PMC article. Updated. Preprint.
-
RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells.Mol Cell. 2017 Jan 19;65(2):272-284. doi: 10.1016/j.molcel.2016.11.030. Mol Cell. 2017. PMID: 28107649 Free PMC article.
-
H3.Y discriminates between HIRA and DAXX chaperone complexes and reveals unexpected insights into human DAXX-H3.3-H4 binding and deposition requirements.Nucleic Acids Res. 2017 Jun 2;45(10):5691-5706. doi: 10.1093/nar/gkx131. Nucleic Acids Res. 2017. PMID: 28334823 Free PMC article.
-
A Molecular Prospective for HIRA Complex Assembly and H3.3-Specific Histone Chaperone Function.J Mol Biol. 2017 Jun 30;429(13):1924-1933. doi: 10.1016/j.jmb.2016.11.010. Epub 2016 Nov 19. J Mol Biol. 2017. PMID: 27871933 Free PMC article. Review.
-
HIRA vs. DAXX: the two axes shaping the histone H3.3 landscape.Exp Mol Med. 2024 Feb;56(2):251-263. doi: 10.1038/s12276-023-01145-3. Epub 2024 Feb 1. Exp Mol Med. 2024. PMID: 38297159 Free PMC article. Review.
Cited by
-
Multifunctional histone variants in genome function.Nat Rev Genet. 2024 Aug 13. doi: 10.1038/s41576-024-00759-1. Online ahead of print. Nat Rev Genet. 2024. PMID: 39138293 Review.
References
-
- Siegel R.L., Miller K.D., Fuchs H.E., Jemal A.. Cancer statistics, 2021. CA Cancer J. Clin. 2021; 71:7–33. - PubMed
-
- Egan A., Dong Y., Zhang H., Qi Y., Balk S.P., Sartor O.. Castration-resistant prostate cancer: adaptive responses in the androgen axis. Cancer Treat. Rev. 2014; 40:426–433. - PubMed
-
- Akamatsu S., Inoue T., Ogawa O., Gleave M.E.. Clinical and molecular features of treatment-related neuroendocrine prostate cancer. Int. J. Urol. 2018; 25:345–351. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Research Materials
Miscellaneous