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Integrative Chemical Biology Approaches to Deciphering the Histone Code: A Problem-Driven Journey
1Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, 999077 China.
Accounts of Chemical Research
|September 23, 2021
Summary
This study develops chemical tools to detect novel histone posttranslational modifications (PTMs) and understand their roles in the "histone code." Findings illuminate how these PTMs regulate chromatin and disease, paving the way for new drug discovery.
Area of Science:
- Epigenetics and Molecular Biology
- Chemical Biology
- Proteomics
Background:
- Genomic DNA in eukaryotes is compacted into chromatin, with histones undergoing posttranslational modifications (PTMs) that regulate DNA-templated processes.
- The "histone code" hypothesis posits that combinations of histone PTMs orchestrate epigenetic regulation and genome stability.
- Many newly identified histone PTMs remain poorly understood, necessitating new methods for their detection and functional analysis.
Purpose of the Study:
- To develop and apply chemical tools to detect novel histone PTMs and elucidate their regulatory mechanisms and biological functions.
- To identify enzymes (writers and erasers) involved in histone PTM regulation and understand their impact on nucleosome and chromatin dynamics.
- To explore the potential of histone PTMs as therapeutic targets for diseases linked to epigenetic dysregulation.
Main Methods:
- Development and application of chemical reporters for detecting negatively charged histone acylations.
- Preparation of homogeneous nucleosomes with acylations for in vitro biophysical analyses.
- Yeast genetic approaches to investigate acylation effects on chromatin dynamics in vivo.
- Establishment of a chemical proteomics platform using photo-cross-linking and quantitative proteomics to identify PTM-interacting proteins (readers and erasers).
- Structure-guided design of inhibitors to manipulate PTM-mediated protein-protein interactions.
Main Results:
- Successful detection of novel histone acylations and characterization of their impact on nucleosome structure and chromatin dynamics.
- Identification of key protein readers and erasers involved in PTM-mediated signaling pathways.
- Demonstration of chemical probes' utility in interrogating histone PTMs and potential for drug discovery.
Conclusions:
- Chemical tools and proteomics strategies are effective for deciphering the roles of novel histone PTMs in the histone code.
- Understanding histone PTMs and their interactions is crucial for comprehending epigenetic regulation and developing disease treatments.
- This work provides a foundation for future research into the complex interplay of histone modifications and their functional consequences.
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