Eed-dependent histone modification orchestrates the iNKT cell developmental program alleviating liver injury

Yun Guo; Shun Ohki; Yohei Kawano; Weng Sheng Kong; Yoshinori Ohno; Hiroaki Honda; Masamoto Kanno; Tomoharu Yasuda

doi:10.3389/fimmu.2024.1467774

Eed-dependent histone modification orchestrates the iNKT cell developmental program alleviating liver injury

Front Immunol. 2024 Sep 20:15:1467774. doi: 10.3389/fimmu.2024.1467774. eCollection 2024.

Authors

Yun Guo¹, Shun Ohki¹, Yohei Kawano¹, Weng Sheng Kong¹, Yoshinori Ohno², Hiroaki Honda³, Masamoto Kanno^{1

4

5}, Tomoharu Yasuda¹

Affiliations

¹ Department of Immunology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
² Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
³ Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Tokyo Women's Medical University, Tokyo, Japan.
⁴ Medical Research and Development Programs Focused on Technology Transfers: Development of Advanced Measurement and Analysis Systems (AMED-SENTAN), Japan Agency for Medical Research and Development, Tokyo, Japan.
⁵ Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo, Japan.

Abstract

Polycomb repressive complex 2 (PRC2) is an evolutionarily conserved epigenetic modifier responsible for tri-methylation of lysine 27 on histone H3 (H3K27me3). Previous studies have linked PRC2 to invariant natural killer T (iNKT) cell development, but its physiological and precise role remained unclear. To address this, we conditionally deleted Eed, a core subunit of PRC2, in mouse T cells. The results showed that Eed-deficient mice exhibited a severe reduction in iNKT cell numbers, particularly NKT1 and NKT17 cells, while conventional T cells and NKT2 cells remained intact. Deletion of Eed disrupted iNKT cell differentiation, leading to increased cell death, which was accompanied by a severe reduction in H3K27me3 levels and abnormal expression of Zbtb16, Cdkn2a, and Cdkn1a. Interestingly, Eed-deficient mice were highly susceptible to acetaminophen-induced liver injury and inflammation in an iNKT cell-dependent manner, highlighting the critical role of Eed-mediated H3K27me3 marks in liver-resident iNKT cells. These findings provide further insight into the epigenetic orchestration of iNKT cell-specific transcriptional programs.

Keywords: Eed; H3K27me3; PRC2; iNKT; liver injury.

MeSH terms

Acetaminophen / adverse effects
Animals
Cell Differentiation
Chemical and Drug Induced Liver Injury / immunology
Chemical and Drug Induced Liver Injury / metabolism
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Epigenesis, Genetic
Histone Code
Histones* / metabolism
Liver / immunology
Liver / metabolism
Liver / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout*
Natural Killer T-Cells* / immunology
Natural Killer T-Cells* / metabolism
Promyelocytic Leukemia Zinc Finger Protein / genetics
Promyelocytic Leukemia Zinc Finger Protein / metabolism

Substances

Histones
Zbtb16 protein, mouse
Acetaminophen
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p16
Cdkn2a protein, mouse
Promyelocytic Leukemia Zinc Finger Protein

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the JSPS KAKENHI under Grant Numbers JP17K17916 to YG, JP18H02669, JP19K22538, and JP21H02751 to TY, by AMED under Grant Numbers 17hm0102012h0005, 18gm0710009h0205, 19gm0710009h0206 to MK.