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

Xusheng Zhang, Xintong Gao, Zhen Liu, Fei Shao, Dou Yu, Min Zhao, Xiwen Qin and Shuo Wang ()
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Xusheng Zhang: Chinese Academy of Sciences
Xintong Gao: Chinese Academy of Sciences
Zhen Liu: Chinese Academy of Sciences
Fei Shao: Chinese Academy of Sciences
Dou Yu: Chinese Academy of Sciences
Min Zhao: Chinese Academy of Sciences
Xiwen Qin: Washington University School of Medicine
Shuo Wang: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Innate lymphoid cell precursors (ILCPs) develop into distinct subsets of innate lymphoid cells (ILCs) with specific functions. The epigenetic program underlying the differentiation of ILCPs into ILC subsets remains poorly understood. Here, we reveal the genome-wide distribution and dynamics of the DNA methylation and hydroxymethylation in ILC subsets and their respective precursors. Additionally, we find that the DNA hydroxymethyltransferase TET1 suppresses ILC1 but not ILC2 or ILC3 differentiation. TET1 deficiency promotes ILC1 differentiation by inhibiting TGF-β signaling. Throughout ILCP differentiation at postnatal stage, gut microbiota contributes to the downregulation of TET1 level. Microbiota decreases the level of cholic acid in the gut, impairs TET1 expression and suppresses DNA hydroxymethylation, ultimately resulting in an expansion of ILC1s. In adult mice, TET1 suppresses the hyperactivation of ILC1s to maintain intestinal homeostasis. Our findings provide insights into the microbiota-mediated epigenetic programming of ILCs, which links microbiota-DNA methylation crosstalk to ILC differentiation.

Date: 2024
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DOI: 10.1038/s41467-024-48794-0

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