A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response

Area of Science:

• Biochemistry
• Epigenetics
• Molecular Biology

Background:

• Jumonji (JMJ) histone demethylases regulate gene transcription and epigenetic inheritance.
• The functional role of JMJ demethylase activity in cellular responses is poorly understood due to a lack of selective inhibitors.
• The KDM6 subfamily (JMJD3 and UTX) specifically demethylates H3K27me3.

Purpose of the Study:

• To elucidate the functional role of the H3K27me3-specific demethylase subfamily (KDM6) using a structure-guided approach.
• To develop the first small-molecule catalytic site inhibitor selective for the H3K27me3-specific JMJ subfamily.
• To investigate the role of JMJD3 and UTX in regulating inflammatory responses.

Main Methods:

• Structure-guided drug design and chemoproteomics.
• Determination of liganded structures for human and mouse JMJD3.
• Generation and testing of a novel small-molecule inhibitor selective for the KDM6 subfamily.
• Assessment of inhibitor efficacy in reducing lipopolysaccharide-induced cytokine production in human macrophages.

Main Results:

• Novel structural insights into cofactor, substrate, and inhibitor recognition by KDM6 demethylases.
• Development of the first selective small-molecule inhibitor targeting the catalytic site of H3K27me3-specific JMJ demethylases.
• Demonstration that the inhibitor binds in a novel manner.
• Significant reduction of proinflammatory cytokine production in human macrophages, dependent on JMJD3 and UTX.
• Clarification of the catalytic function of H3K27-specific JMJs in inflammatory responses.

Conclusions:

• The study resolves ambiguity regarding the catalytic function of H3K27-specific JMJs in disease-relevant inflammatory responses.
• The developed small-molecule inhibitor provides a valuable tool for pharmacological intervention.
• These findings encourage the design of selective inhibitors for the broader JMJ family for therapeutic applications.