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

Beyaz, S., Kim, J. H., Pinello, L., Xifaras, M. E., Hu, Y., Huang, J., Kerenyi, M. A., Das, P. P., Barnitz, R. A., Herault, A., Dogum, R., Haining, W. N., Yilmaz, O. H., Passegue, E., Yuan, G. C., Orkin, S. H., Winau, F. (February 2017) The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. Nat Immunol, 18 (2). pp. 184-195. ISSN 1529-2916 (Electronic)1529-2908 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/27992400
DOI: 10.1038/ni.3644

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.

Item Type: Paper
Uncontrolled Keywords: Animals *Cell Differentiation Cell Lineage Cells, Cultured Enhancer Elements, Genetic/genetics *Epigenesis, Genetic *Gene Expression Regulation Histone Demethylases/genetics/*metabolism Immunity, Innate/genetics Kruppel-Like Transcription Factors/genetics/metabolism Mice Mice, Inbred C57BL Natural Killer T-Cells/*physiology Organ Specificity Promoter Regions, Genetic/genetics Promyelocytic Leukemia Zinc Finger Protein Transcription Factors/genetics/metabolism
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation
Investigative techniques and equipment > cell lineage tracing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Beyaz lab
Depositing User: Matt Covey
Date: February 2017
Date Deposited: 02 Feb 2018 19:56
Last Modified: 02 Feb 2018 19:56
PMCID: PMC5247321
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36046

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