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

Semir Beyaz; Ji Hyung Kim; Luca Pinello; Michael E. Xifaras; Yu Hu; Jialiang Huang; Marc A. Kerenyi; Partha P. Das; R. Anthony Barnitz; Aurelie Herault; Rizkullah Dogum; W. Nicholas Haining; Ömer H. Yilmaz; Emmanuelle Passegue; Guo Cheng Yuan; Stuart H. Orkin; Florian Winau

doi:10.1038/ni.3644

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

Semir Beyaz, Ji Hyung Kim, Luca Pinello, Michael E. Xifaras, Yu Hu, Jialiang Huang, Marc A. Kerenyi, Partha P. Das, R. Anthony Barnitz, Aurelie Herault, Rizkullah Dogum, W. Nicholas Haining, Ömer H. Yilmaz, Emmanuelle Passegue, Guo Cheng Yuan, Stuart H. Orkin, Florian Winau

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

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.

Original language	English
Pages (from-to)	184-195
Number of pages	12
Journal	Nature Immunology
Volume	18
Issue number	2
DOIs	https://doi.org/10.1038/ni.3644
Publication status	Published - 2017 Feb 1
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ni.3644

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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, Ö. H., Passegue, E., Yuan, G. C., Orkin, S. H., & Winau, F. (2017). The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. Nature Immunology, 18(2), 184-195. https://doi.org/10.1038/ni.3644

Beyaz, S, Kim, JH, Pinello, L, Xifaras, ME, Hu, Y, Huang, J, Kerenyi, MA, Das, PP, Barnitz, RA, Herault, A, Dogum, R, Haining, WN, Yilmaz, ÖH, Passegue, E, Yuan, GC, Orkin, SH & Winau, F 2017, 'The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells', Nature Immunology, vol. 18, no. 2, pp. 184-195. https://doi.org/10.1038/ni.3644

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

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.",

author = "Semir Beyaz and Kim, {Ji Hyung} and Luca Pinello and Xifaras, {Michael E.} and Yu Hu and Jialiang Huang and Kerenyi, {Marc A.} and Das, {Partha P.} and Barnitz, {R. Anthony} and Aurelie Herault and Rizkullah Dogum and Haining, {W. Nicholas} and Yilmaz, {{\"O}mer H.} and Emmanuelle Passegue and Yuan, {Guo Cheng} and Orkin, {Stuart H.} and Florian Winau",

note = "Funding Information: the National Research Foundation of Korea (2012R1A6A3A03040248 to J.H.K.) Publisher Copyright: {\textcopyright} 2017 nature America, Inc., part of Springer Nature. All rights reserved.",

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AU - Kerenyi, Marc A.

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AU - Dogum, Rizkullah

AU - Haining, W. Nicholas

AU - Yilmaz, Ömer H.

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AU - Yuan, Guo Cheng

AU - Orkin, Stuart H.

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

Abstract

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