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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.

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Figure 1: H3K27 demethylases are essential for the maturation and development of iNKT cells.
Figure 2: UTX is required for the lineage-specific expression of signature genes in iNKT cell development.
Figure 3: UTX regulates the chromatin landscape of iNKT cells.
Figure 4: UTX occupies the promoters of iNKT cell signature genes that exhibit UTX-dependent chromatin regulation.
Figure 5: The demethylase activity of UTX is required for the generation of iNKT cells.
Figure 6: JunB partners with UTX to regulate the iNKT cell signature and development.
Figure 7: UTX deficiency impairs the activation of PLZF target genes in iNKT cells.
Figure 8: UTX facilitates the accessibility of super-enhancers in iNKT cells.

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Acknowledgements

We thank the US National Institutes of Health Tetramer Facility for CD1d-tetramers, the Center for Cancer Computational Biology sequencing facility at the Dana-Farber Cancer Institute for Illumina HiSeq2000 sequencing, the Microarray core facility at the Dana-Farber Cancer Institute Molecular Biology Core Facilities for microarray analysis, and the Dana-Farber Cancer Institute Jimmy Fund FACS core facility for cell sorting. Supported by the Howard Hughes Medical Institute (S.H.O.), the US National Institutes of Health (P30DK0492 to S.H.O., and RO1 AI083426 to F.W.), the Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology (S.B.), the National Research Foundation of Korea (2012R1A6A3A03040248 to J.H.K.) and the National Human Genome Research Institute of the US National Institutes of Health (Career Development Award K99HG008399 to L.P.).

Author information

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Authors

Contributions

S.B. designed, performed and interpreted experiments involving gene expression analysis, ChIP-Seq, ATAC-Seq, lentiviral transduction, qRT-PCR, ChIP-PCR and immunoprecipitation, with help from M.E.X., and generated UTX-KO and JMJD3-KO mice, with help from M.A.K.; J.H.K. designed, performed and interpreted experiments involving iNKT cell analysis by flow cytometry with help from Y.H.; L.P. designed, performed and interpreted bioinformatics analysis with help from J.H.; P.P.D., R.A.B. and R.D. assisted with ChIP-Seq analysis; A.H. and E.P. provided JunB-KO mice; W.N.H. and Ö.H.Y. participated in the design and interpretation of experiments; G.-C.Y. supervised bioinformatics analysis; S.H.O. and F.W. designed and supervised experiments; and S.B., J.H.K., S.H.O. and F.W. wrote the manuscript with support from L.P.

Corresponding authors

Correspondence to Stuart H Orkin or Florian Winau.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Generation of UTX-KO and JMJD3-KO mice.

(a) Utx locus in UTX-targeted embryonic stem cells (ESCs) that were provided from EUCOMM. (b) PCR analysis verifying loxP sites targeting exon 3 of Utx in ESC clones. (c) Targeting strategy for Jmjd3 locus to delete exons 17-19. (d) Southern blot analysis of Jmjd3-targeted ESC clones. (e) Representative genotyping of conditional UTX-or JMJD3-KO mice. (f) Analysis of Utx or Jmjd3 mRNA levels in blood, DP thymocytes, or iNKT cells by qRT-PCR using deletion-specific primers. Data are mean ± s.d. from three independent experiments.

Supplementary Figure 2 UTX is required for development of iNKT cells but not for their function.

(a) Conditional UTX-deficient (UTX KO) mice or wild-type (WT) littermates were injected intraperitoneally with 2 μg α-GalCer. Two hours later, lymphocytes from thymus and liver were collected for intracellular staining of IFN-γ and IL-4, prior to analysis by flow cytometry. Additionally, thymic iNKT cells were restimulated with PMA and Ionomycin for 4 hours before analysis. (b) Flow cytometry analysis of WT or UTX KO thymic iNKT cells by measurement of transcription factors T-bet, PLZF, and RORγt, gated on CD1d-tetramer+ cells. Shown are the absolute cell counts of NKT1, NKT2, or NKT17 cells among thymic iNKT cells from WT or UTX KO (n = 3). (c) Analysis of CD1d expression on DP thymocytes from WT or UTX KO mice using flow cytometry. (d) DP thymocytes were isolated from WT or UTX KO mice. Subsequently, mRNA transcripts of Vα14-Jα18 TCR were analyzed by qRT-PCR and normalized to constant alpha chain (Cα) amplification. Y-axis depicts relative expression (n = 5). Results in (b-d) are representative of three independent experiments. Data are mean ± s.e.m. **P < 0.01 as analyzed by unpaired t-test.

Supplementary Figure 3 Characterization of gene-expression alterations in control and UTX-KO thymic iNKT cells.

(a) Heat map of gene expression microarray (WT; n=5, KO; n=4). (b) GSEA of downregulated or (c) upregulated genes in UTX-deficient (KO) iNKT cells compared to wild-type (WT). ES, enrichment score; NES, normalized ES; FDR, false discovery rate. (d) iNKT cells in stage 0 and stage 1-3 have reduced signature gene expression in UTX KO as assessed by qRT-PCR. (e) Confirming the loss of UTX transcripts in stage 0 and stage 1-3 iNKT cells in UTX KO as assessed by qRT-PCR. Data are mean ± s.d. from three independent experiments.

Supplementary Figure 4 Distribution of H3K27me3 regions in control and UTX-KO iNKT cells.

(a,b) Chromosomal distribution of WT-specific (a) or UTX-KO-specific (b) H3K27me3 peaks in iNKT cells. (c,d) Distribution of WT-specific (c) or UTX-KO-specific (d) H3K27me3 peaks within the genome of iNKT cells.

Supplementary Figure 5 Characterization of regions with H3K27me3 peaks in control and UTX-KO iNKT cells.

(a) GREAT analysis of WT-specific H3K27me3 peaks (n = 4,250). (b) GREAT analysis of UTX KO-specific H3K27me3 peaks (n = 9,645). (c,d) Assessing statistical significance of H3K27me3 distribution around the promoters of downregulated (c) and upregulated (d) genes between WT and UTX-deficient (KO) iNKT cells based on permutation test where 100,000 permutations were used to calculate the distribution of the difference between two average profiles. Black line depicts empirical null model, dotted red line indicates the observed value for the measured profiles. (e,f) GREAT analysis of all downregulated (e) or upregulated (f) genes in UTX KO iNKT cells compared to WT controls.

Supplementary Figure 6 Cluster analysis of the chromatin landscape around gene promoters in control or UTX-KO iNKT cells.

Heat maps represent the abundance of H3K4me3 and H3K27me3 marks around the promoters of downregulated (a) or upregulated genes (b) in UTX-deficient (KO) iNKT cells compared to wild-type (WT). Genes are subdivided into different clusters dependent on their histone mark pattern. C1-4 = clusters 1 to 4. (c) Integrating gene expression with chromatin state for upregulated genes. Average abundance of H3K27me3 and H3K4me3 around upregulated gene promoters is depicted as z-score in reads per million (rpm). Average profiles are grouped in three clusters of upregulated genes with WT in blue and KO in green. The upper panel shows expression of upregulated genes as logarithmic fold change (log2FC). (d) GREAT analysis of downregulated genes in UTX-deficient iNKT cells in cluster 3 and cluster 4.

Supplementary Figure 7 Intrinsic function of UTX is responsible for development of iNKT cells.

Mixed bone marrow-chimeric mice were generated using a 1:1 ratio of wild-type (WT) and conditional UTX-deficient (KO) bone marrow cells for transfer into Rag2-/- hosts (n = 5). Twelve weeks later, WT cells were detected by anti-CD45.1, and frequencies of thymic iNKT cells were analyzed by flow cytometry. (a) Depicted are the ratios of WT to KO iNKT cells gated on the different maturational stages. (b) Bar graph depicting the results from (a). (c) In the same experiment as described in (a), lymphocytes from liver were analyzed for iNKT cells (CD3+tetramer+) as well as conventional T cells (CD3+tetramer-). Depicted are the ratios of WT to KO T lymphocytes. Results are representative of two independent experiments.

Supplementary Figure 8 Characterization of iNKT cell super-enhancers.

(a,b) Epigenetic landscape of the super-enhancers for Tbx21 (a) and Il2rb (b) that exhibit UTX-dependent accessibility. Depicted are the ChIP-Seq tracks of H3K27ac and heat maps of ATAC-Seq, H3K27me3, and H3K4me3 in WT or UTX-deficient (KO) iNKT cells around the super-enhancer (SE) for Tbx21 (a) and Il2rb (b). Zoomed in tracks in Fig. 8f and Fig. 8g are shown in black rectangle and highlighted with a star. (c) GREAT analysis of the super-enhancer elements in iNKT cells. (d) GREAT analysis of the SE elements in iNKT cells that exhibit UTX-dependent accessibility. (e) Transcription factor target motif analysis using Haystack in iNKT cell SE elements that exhibit UTX-dependent accessibility. Depicted are the binding motifs of RELA and BHLHE40.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 1767 kb)

Supplementary Table 1

List of genes that exhibit UTX-dependent chromatin regulation in cluster 3 and cluster 4 (XLS 47 kb)

Supplementary Table 2

List of JunB target genes in cluster 3 (XLSX 12 kb)

Supplementary Table 3

List of iNKT super enhancers (XLSX 59 kb)

Supplementary Table 4

List of super-enhancer regions that lost accessibility in UTX-KO (WT-specific) or gained accessibility in UTX-KO (KO-specific) (XLS 34 kb)

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Beyaz, S., Kim, J., Pinello, L. et al. The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. Nat Immunol 18, 184–195 (2017). https://doi.org/10.1038/ni.3644

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