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Published on: April 5, 2018
Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer
Yumei Wang1, Haiyan Wang2, Wei Shao3
1School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Objective:
Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression; however, the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive. It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets.
Methods:
We employed high-throughput sequencing-based high-throughput screening (HTS2) to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators. Then, bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer.
Results:
Utilizing these gene expression signatures, we classified the epigenetic regulators into five distinct clusters, each characterized by specific functions. We discovered functional similarities between BAZ2B and SETMAR, as well as CLOCK and CBX3. Moreover, we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation. Notably, we constructed an epigenetic regulatory network based on the gene expression signatures, which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer.
Conclusions:
Our work deciphered the extensive regulation among hundreds of epigenetic regulators. The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.
Insights
This study deciphers the complex epigenetic regulatory network in breast cancer, identifying 10 master regulators crucial for gene expression. These findings offer potential new therapeutic targets for breast cancer treatment.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Epigenetic abnormalities are key drivers of breast cancer gene expression.
- The full scope of epigenetic regulator interactions in breast cancer is not well understood.
- Identifying master regulators is crucial for developing targeted breast cancer therapies.
Purpose of the Study:
- To comprehensively map the epigenetic regulatory network in breast cancer.
- To identify key epigenetic regulators and potential therapeutic targets.
- To understand the functional relationships among hundreds of epigenetic regulators.
Main Methods:
- High-throughput sequencing-based high-throughput screening (HTS²) was used to analyze gene expression changes.
- The study examined the impact of knocking down 400 epigenetic regulators on 2,986 genes.
- Bioinformatics tools were applied to gene expression signatures for network analysis.
Main Results:
- Epigenetic regulators were classified into five functional clusters.
- Functional similarities were found between BAZ2B/SETMAR and CLOCK/CBX3.
- An epigenetic regulatory network revealed 8 modules and identified 10 master epigenetic regulators in breast cancer.
Conclusions:
- This research elucidates the extensive regulatory roles of hundreds of epigenetic regulators in breast cancer.
- Ten master epigenetic regulators were identified as promising therapeutic targets.
- The study provides a foundation for novel breast cancer treatment strategies targeting epigenetic mechanisms.
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