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

Cell & Bioscience
Daniel NorthrupKeji Zhao

Abstract

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 i...Continue Reading

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Citations

Jan 11, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Takeshi YamadaMasakatsu Yamashita
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Jan 29, 2020·Annual Review of Immunology·Michael J Shapiro, Virginia Smith Shapiro
Apr 18, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tianhao XuGustavo J Martinez
May 1, 2021·Biochemical Society Transactions·Christine R Keenan
Aug 21, 2020·Molecular and Cellular Biology·Nhien TranKai Ge

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Methods Mentioned

BETA
flow cytometry
FACS
Flow
PCR
light microscopy
RNA-Seq
ChIP-seq

Software Mentioned

HOMER
Bowtie aligner
Bowtie
FindMotifsGenome

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