Microbiota regulates the TET1-mediated DNA hydroxymethylation program in innate lymphoid cell differentiation

Area of Science:

• Immunology
• Epigenetics
• Microbiology

Background:

• Innate lymphoid cells (ILCs) are crucial for immune responses.
• The epigenetic mechanisms governing ILC differentiation from precursors (ILCPs) are not fully understood.

Purpose of the Study:

• To investigate the genome-wide DNA methylation and hydroxymethylation dynamics during ILC differentiation.
• To elucidate the role of TET1 in ILC subset specification and the influence of gut microbiota on this process.

Main Methods:

• Genome-wide DNA methylation and hydroxymethylation profiling in ILC subsets and precursors.
• Analysis of TET1 function in ILC differentiation using genetic models.
• Investigation of microbiota-induced changes in TET1 expression and epigenetic modifications.

Main Results:

• TET1 suppresses ILC1 differentiation, while its deficiency promotes it by inhibiting TGF-β signaling.
• Gut microbiota downregulates TET1 levels during postnatal ILCP differentiation, leading to ILC1 expansion.
• TET1 maintains intestinal homeostasis by suppressing ILC1 hyperactivation in adult mice.

Conclusions:

• Gut microbiota epigenetically programs ILC differentiation through TET1-mediated DNA hydroxymethylation.
• This study reveals a crosstalk between microbiota, DNA methylation, and ILC development, impacting immune homeostasis.