A new horizon for epigenetic medicine?
1Division of Newborn Medicine and Program in Epigenetics, Department of Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston MA, 02115, USA.
Cell Research
|September 19, 2012
Summary
Researchers identified chemical inhibitors for histone demethylases KDM6A and KDM6B, crucial in inflammation and cancer. These inhibitors selectively block gene transcription involved in inflammatory processes by modifying H3K27me3 levels.
Area of Science:
- Epigenetics and Molecular Biology
- Drug Discovery and Development
Background:
- Histone lysine demethylases (KDM) are critical chromatin modifiers.
- Dysregulation of KDMs is implicated in pathological processes like cancer and inflammation.
- KDM6A and KDM6B (UTX and JMJD3) are key histone H3 lysine 27 demethylases.
Purpose of the Study:
- To identify and validate chemical inhibitors targeting KDM6A and KDM6B.
- To demonstrate the potential of KDM6 inhibition as a therapeutic strategy.
- To investigate the effects of KDM6 inhibition on gene transcription and chromatin modification.
Main Methods:
- Chemical screening for KDM6A/KDM6B inhibitors.
- Biochemical assays to assess demethylase activity and selectivity.
- Cell-based assays to evaluate gene expression changes and H3K27me3 levels.
Main Results:
- Identification of chemical matter that inhibits KDM6A and KDM6B demethylase activity.
- Demonstration of remarkable substrate selectivity for the identified inhibitors.
- Inhibition of pro-inflammatory gene transcription in cell culture by altering H3K27me3 levels.
Conclusions:
- KDM6A and KDM6B are validated as druggable targets.
- Selective KDM6 inhibition offers a potential therapeutic approach for inflammatory diseases.
- Targeting histone demethylases represents a promising strategy in epigenetic drug discovery.
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