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Cell Biosci. 2017 May 17;7:25. doi: 10.1186/s13578-017-0152-8. eCollection 2017.

Histone demethylases UTX and JMJD3 are required for NKT cell development in mice.

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Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892 USA.
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892 USA.
Center of Immunology, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892 USA.
Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892 USA.
Departments of Pathology and Immunology, Center for Cell and Gene Therapy, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030 USA.
Contributed equally



Natural killer (NK)T cells and conventional T cells share phenotypic characteristic however they differ in transcription factor requirements and functional properties. The role of histone modifying enzymes in conventional T cell development has been extensively studied, little is known about the function of enzymes regulating histone methylation in NKT cells.


We show that conditional deletion of histone demethylases UTX and JMJD3 by CD4-Cre leads to near complete loss of liver NKT cells, while conventional T cells are less affected. Loss of NKT cells is cell intrinsic and not due to an insufficient selection environment. The absence of NKT cells in UTX/JMJD3-deficient mice protects mice from concanavalin A-induced liver injury, a model of NKT-mediated hepatitis. GO-analysis of RNA-seq data indicates that cell cycle genes are downregulated in UTX/JMJD3-deleted NKT progenitors, and suggest that failed expansion may account for some of the cellular deficiency. The phenotype appears to be demethylase-dependent, because UTY, a homolog of UTX that lacks catalytic function, is not sufficient to restore their development and removal of H3K27me3 by deletion of EZH2 partially rescues the defect.


NKT cell development and gene expression is sensitive to proper regulation of H3K27 methylation. The H3K27me3 demethylase enzymes, in particular UTX, promote NKT cell development, and are required for effective NKT function.

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