Distinct modulation of IFNgamma-induced transcription by BET bromodomain and catalytic P300/CBP inhibition in breast cancer
- Author(s)
- Hogg, SJ; Motorna, O; Kearney, CJ; Derrick, EB; House, IG; Todorovski, I; Kelly, MJ; Zethoven, M; Bromberg, KD; Lai, A; Beavis, PA; Shortt, J; Johnstone, RW; Vervoort, SJ;
- Journal Title
- Clinical Epigenetics
- Publication Type
- Research article
- Abstract
- BACKGROUND: Interferon gamma (IFNgamma) is a pro-inflammatory cytokine that directly activates the JAK/STAT pathway. However, the temporal dynamics of chromatin remodeling and transcriptional activation initiated by IFNgamma have not been systematically profiled in an unbiased manner. Herein, we integrated transcriptomic and epigenomic profiling to characterize the acute epigenetic changes induced by IFNgamma stimulation in a murine breast cancer model. RESULTS: We identified de novo activation of cis-regulatory elements bound by Irf1 that were characterized by increased chromatin accessibility, differential usage of pro-inflammatory enhancers, and downstream recruitment of BET proteins and RNA polymerase II. To functionally validate this hierarchical model of IFNgamma-driven transcription, we applied selective antagonists of histone acetyltransferases P300/CBP or acetyl-lysine readers of the BET family. This highlighted that histone acetylation is an antecedent event in IFNgamma-driven transcription, whereby targeting of P300/CBP acetyltransferase activity but not BET inhibition could curtail the epigenetic remodeling induced by IFNgamma through suppression of Irf1 transactivation. CONCLUSIONS: These data highlight the ability for epigenetic therapies to reprogram pro-inflammatory gene expression, which may have therapeutic implications for anti-tumor immunity and inflammatory diseases.
- Keywords
- Acetylation; Animals; *Breast Neoplasms/drug therapy/genetics; DNA Methylation; E1A-Associated p300 Protein; Female; *Interferon-gamma/pharmacology; Janus Kinases; Membrane Proteins; Mice; Phosphoproteins; STAT Transcription Factors; Signal Transduction; Bromodomain; Enhancer; H3k27ac; Histone acetylation; Immuno-oncology; Inflammation; Interferon; P300/cbp
- Department(s)
- Laboratory Research
- PubMed ID
- 35902886
- Publisher's Version
- https://doi.org/10.1186/s13148-022-01316-5
- Open Access at Publisher's Site
https://doi.org/10.1186/s13148-022-01316-5- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-11-01 07:00:18
Last Modified: 2024-11-01 07:00:55