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Generation and Purification of Human INO80 Chromatin Remodeling Complexes and Subcomplexes
Published on: October 23, 2014
Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis
Gabriel J Sandoval1, John L Pulice2, Hubert Pakula3
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Abstract:
Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.
Insights
The ETS-related gene (ERG) protein interacts with the BAF chromatin remodeling complex in prostate cancer. This interaction is crucial for ERG to control gene expression and drive cancer cell growth.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Prostate cancer frequently involves rearrangements fusing TMPRSS2 with the ETS family transcription factor ERG.
- The precise mechanisms by which ERG drives oncogenic gene expression and proliferation are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying ERG's role in prostate cancer.
- To identify potential interactions between ERG and cellular machinery involved in gene regulation.
Main Methods:
- Chromatin immunoprecipitation (ChIP) assays to assess ERG and BAF complex occupancy.
- Prostate organoid models to study ERG function in a relevant biological context.
- Biochemical assays to determine the dependence of ERG on BAF complex activity.
Main Results:
- A direct binding interaction was identified between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex.
- ERG binding to the ETS DNA motif mediates genome-wide retargeting of BAF complexes.
- ERG requires intact BAF complexes and their ATPase activity for chromatin occupancy and target gene regulation.
- In prostate organoids, BAF complexes are essential for ERG-driven basal-to-luminal cell transition.
Conclusions:
- ERG and BAF chromatin remodeling complexes exhibit a fundamental interdependence in prostate cancer.
- This interaction is conserved across other oncogenic ETS factors.
- Targeting the ERG-BAF interaction may offer new therapeutic strategies for prostate cancer.
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