The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

Nat Immunol. 2017 Feb;18(2):184-195. doi: 10.1038/ni.3644. Epub 2016 Dec 19.

Abstract

Invariant natural killer T cells (iNKT cells) are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about the epigenetic regulation of iNKT cell development. Here we found that the H3K27me3 histone demethylase UTX was an essential cell-intrinsic factor that controlled an iNKT-cell lineage-specific gene-expression program and epigenetic landscape in a demethylase-activity-dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT cell signature genes due to a decrease in activation-associated H3K4me3 marks and an increase in repressive H3K27me3 marks within the promoters occupied by UTX. We found that JunB regulated iNKT cell development and that the expression of genes that were targets of both JunB and the iNKT cell master transcription factor PLZF was UTX dependent. We identified iNKT cell super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for commitment to the iNKT cell lineage. Our findings reveal how UTX regulates the development of iNKT cells through multiple epigenetic mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Lineage
  • Cells, Cultured
  • Enhancer Elements, Genetic / genetics
  • Epigenesis, Genetic*
  • Gene Expression Regulation*
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism*
  • Immunity, Innate / genetics
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Natural Killer T-Cells / physiology*
  • Organ Specificity
  • Promoter Regions, Genetic / genetics
  • Promyelocytic Leukemia Zinc Finger Protein
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • JunB protein, mouse
  • Kruppel-Like Transcription Factors
  • Promyelocytic Leukemia Zinc Finger Protein
  • Transcription Factors
  • Zbtb16 protein, mouse
  • Histone Demethylases
  • Utx protein, mouse