DNA methylation and histone modifications drive the trained immunity duration

Area of Science:

• Immunology
• Epigenetics
• Cell Biology

Background:

• Trained immunity (TRIM) represents a form of innate immune memory.
• Histone modifications are implicated in TRIM but struggle to explain its long-term persistence due to reversibility and dilution.
• Existing mechanisms do not fully account for the enduring nature of trained immunity.

Purpose of the Study:

• To investigate the role of DNA methylation in the long-term persistence of trained immunity.
• To propose DNA methylation as a key epigenetic mechanism underlying TRIM.
• To elucidate how DNA methylation contributes to the stability and inheritance of trained immunity.

Main Methods:

• Analysis of epigenetic modifications in immune cells.
• Investigating DNA methylation patterns at proinflammatory gene loci.
• Studying the inheritance of epigenetic marks through cell division.

Main Results:

• DNA methylation patterns, particularly hypomethylation at proinflammatory gene loci, are proposed as a key mechanism for long-term TRIM.
• Hypomethylated states are biochemically stable and heritable through cell division.
• These states facilitate rapid accumulation of activating histone marks upon restimulation.

Conclusions:

• DNA methylation-mediated processes are crucial for the durability of trained immunity.
• This mechanism explains TRIM's persistence across various cellular contexts, including stem cell renewal and tissue-resident cells.
• Epigenetic stability via DNA methylation underpins the long-lasting effects of innate immune training.