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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
E2F1 K117 methylation by SETD6 disrupts BRD4-E2F1 binding and modulates E2F1 chromatin binding and gene regulation in
Gizem Tugce Ulu1, Margarita Kublanovsky2,3, Raz Shalev2,3
1Institute of Biochemistry, University of Stuttgart, Allmandring 31, Stuttgart 70569, Germany.
Abstract:
The SETD6 (SET domain-containing protein 6) protein lysine methyltransferase regulates various cellular processes including cancer initiation and progression. It monomethylates the transcription factor E2F1 (E2F transcription factor 1) and several other important proteins, but the functional consequences of many SETD6 mediated methylation events are unknown. In this study, the role of SETD6 mediated K117 monomethylation of E2F1 was investigated in prostate cancer cells. In chromatin binding and gene expression experiments, we identified distinct sets of genes that are bound and upregulated by methylated and unmethylated E2F1 indicating that E2F1 methylation by SETD6 directly modulates its chromatin interaction. In agreement with these findings, cellular data showed that E2F1 methylation affects oncogenic phenotypes. Mechanistically, we demonstrate with biochemical, cellular, and genomic assays that SETD6-mediated K117 methylation directly regulates the interaction of E2F1 and BRD4 by preventing K117 acetylation. Our data suggest that K117 methylation/acetylation represents a switch controlling bromodomain binding to E2F1 by which SETD6 methylation regulates different cellular effects of E2F1. Similar mechanisms may apply to the regulation of other transcription factors by SETD6.
Insights
SETD6 protein lysine methyltransferase monomethylates transcription factor E2F1, impacting gene regulation and oncogenic phenotypes in prostate cancer. This methylation switch controls E2F1
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Research
Background:
- SETD6 (SET domain-containing protein 6) is a lysine methyltransferase involved in cellular processes, including cancer.
- SETD6 monomethylates the transcription factor E2F1, but the functional outcomes remain largely unknown.
- E2F1 plays a critical role in cell cycle regulation and cancer development.
Purpose of the Study:
- To investigate the role of SETD6-mediated E2F1 K117 monomethylation in prostate cancer.
- To elucidate the mechanism by which SETD6 methylation affects E2F1 function and chromatin interaction.
- To determine the impact of E2F1 methylation on oncogenic phenotypes.
Main Methods:
- Chromatin binding assays
- Gene expression analysis
- Biochemical and cellular assays
- Genomic assays
Main Results:
- SETD6-mediated E2F1 methylation alters E2F1's chromatin binding and gene upregulation profiles.
- E2F1 methylation by SETD6 influences oncogenic phenotypes in prostate cancer cells.
- SETD6-mediated K117 methylation prevents E2F1 K117 acetylation, regulating E2F1-BRD4 interaction.
Conclusions:
- SETD6-mediated K117 methylation acts as a molecular switch, controlling E2F1's interaction with BRD4 via a methylation/acetylation mechanism.
- This regulatory switch modulates E2F1's chromatin binding and downstream gene expression, affecting cellular phenotypes.
- The findings suggest a broader role for SETD6 in regulating transcription factor activity through similar methylation/acetylation mechanisms.
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