H3K27-specific demethylase orchestrates the phenotypic and functional plasticity of intestinal ILC3s.

Area of Science:

• Immunology
• Epigenetics
• Cell Biology

Background:

• Group 3 innate lymphoid cells (ILC3s) are crucial for mucosal immunity and exhibit plasticity.
• Epigenetic mechanisms, including histone modifications, control ILC3 differentiation and function.

Purpose of the Study:

• To investigate the role of histone demethylases UTX and JMJD3 in ILC3 specialization.
• To elucidate the epigenetic mechanisms governing ILC3 subset balance and function.

Main Methods:

• Utilized single-cell profiling to analyze ILC3 differentiation trajectories.
• Employed Cleavage under targets and tagmentation (CUT&Tag) to map UTX binding sites.
• Performed retroviral reconstitution to assess the function of TCF7.

Main Results:

• UTX and JMJD3 deficiency led to depletion of NKp46+ ILC3s and expansion of CCR6+ ILC3s.
• Epigenetic reprogramming by UTX/JMJD3 ablation altered ILC3 lineage commitment.
• UTX directly regulates Tcf7 expression by demethylating H3K27me3 at its enhancer regions.
• TCF7 acts as a key downstream effector of UTX in ILC3 differentiation.

Conclusions:

• UTX and JMJD3 are critical epigenetic regulators of ILC3 subset balance and function.
• These findings highlight the UTX-TCF7 axis in controlling mucosal immunity.
• Targeting UTX/JMJD3 offers potential therapeutic strategies for ILC3-related inflammatory disorders.