Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• Myeloid-derived suppressor cells (MDSCs) exacerbate sepsis by inducing immunosuppression.
• MDSC development in sepsis is linked to the long non-coding RNA Hotairm1 and S100A9.
• Epigenetic regulation of gene expression plays a critical role in immune cell function during sepsis.

Purpose of the Study:

• To investigate the role of histone demethylase KDM6A in regulating Hotairm1 transcription during sepsis.
• To evaluate the therapeutic potential of targeting KDM6A with GSK-J4 to modulate MDSC function in sepsis.
• To explore the translational relevance of KDM6A inhibition in human sepsis.

Main Methods:

• Utilized a mouse model simulating sepsis immunobiology.
• Employed chemical inhibition of KDM6A using GSK-J4.
• Analyzed histone modifications (H3K27me3, H3K4me3), transcription factor binding (PU.1), and cytokine levels (IL-10).
• Ex vivo experiments with MDSCs from human sepsis patients.

Main Results:

• KDM6A promotes Hotairm1 transcription by removing the repressive H3K27me3 mark.
• GSK-J4 treatment represses Hotairm1 transcription, reduces H3K4me3, and decreases PU.1 binding.
• IL-10 enhances KDM6A binding to the Hotairm1 promoter; IL-10 knockdown reverses these effects.
• GSK-J4 treatment causes S100A9 relocalization from the nucleus to the cytosol.
• Inhibiting KDM6A ex vivo in human sepsis MDSCs decreases Hotairm1 transcription.

Conclusions:

• KDM6A epigenetically regulates Hotairm1 transcription, a key factor in sepsis-induced MDSC immunosuppression.
• Targeting KDM6A with GSK-J4 offers a potential strategy to reverse MDSC-mediated immunosuppression in sepsis.
• Epigenetic modulation of MDSCs presents a promising therapeutic avenue for improving sepsis outcomes in humans.