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Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments

A Publisher Correction to this article was published on 15 January 2019

This article has been updated


Accumulation of trimethylation of histone H3 at lysine 4 (H3K4me3) on immune-related gene promoters underlies robust transcription during trained immunity. However, the molecular basis for this remains unknown. Here we show three-dimensional chromatin topology enables immune genes to engage in chromosomal contacts with a subset of long noncoding RNAs (lncRNAs) we have defined as immune gene–priming lncRNAs (IPLs). We show that the prototypical IPL, UMLILO, acts in cis to direct the WD repeat-containing protein 5 (WDR5)–mixed lineage leukemia protein 1 (MLL1) complex across the chemokine promoters, facilitating their H3K4me3 epigenetic priming. This mechanism is shared amongst several trained immune genes. Training mediated by β-glucan epigenetically reprograms immune genes by upregulating IPLs in manner dependent on nuclear factor of activated T cells. The murine chemokine topologically associating domain lacks an IPL, and the Cxcl genes are not trained. Strikingly, the insertion of UMLILO into the chemokine topologically associating domain in mouse macrophages resulted in training of Cxcl genes. This provides strong evidence that lncRNA-mediated regulation is central to the establishment of trained immunity.

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Fig. 1: Chromatin 3D structure brings H3K4me3-primed TNF-responsive genes proximal to IPLs.
Fig. 2: UMLILO is a new super-enhancer-resident lncRNA that is transcribed within the ELR + CXC chemokine TAD.
Fig. 3: The UMLILO lncRNA regulates H3K4me3 across the CXCL chemokine promoters.
Fig. 4: UMLILO interacts with WDR5.
Fig. 5: UMLILO acts in cis to regulate chemokine transcription.
Fig. 6: WDR5–lncRNA regulation is a general mechanism of H3K4me3-primed TNF-responsive genes.
Fig. 7: β-Glucan epigenetically reprograms immune genes by upregulating IPLs in a NFAT-dependent manner.
Fig. 8: Inserting UMLILO within the mouse chemokine TAD restored training of the Cxcl chemokines.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. RNA-seq data are available in the Gene Expression Omnibus under accession number GSE120621.

Change history

  • 15 January 2019

    In the version of this article initially published, ‘+’ and ‘–’ labels were missing from the graph keys at the bottom of Fig. 8d. The error has been corrected in the HTML and PDF versions of the article.


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We thank all members of the Gene Expression and Biophysics Laboratory (the M.M.M. laboratory). We thank M. Lusic, A Gontijo, F. Brombacher, Y. Negishi, L. Davignon and INTRIM consortium members for comments on the manuscript. The authors also thank S. Consalvi, M. Charpentier, A. Boucharlat and the Chemogenomic and Biological screening core facility at the Institut Pasteur in Paris for support during the course of this work. This research is supported by a Department of Science and Technology Centre of Competence Grant, an SA Medical Research Council SHIP grant, and a CSIR Parliamentary Grant, all to M.M.M., and M.M.M. is a Chan Zuckerberg Investigator of the Chan Zuckerberg Initiative. A full list of the investigators who contributed to the generation of the Blueprint Consortium data used in the ChIP-seq project is available from Funding for that project was provided by the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement number 282510–BLUEPRINT.

Author information




S.F. and M.M.M. designed the study. S.F. performed most experiments and collected and analyzed data. E.T.F. carried out 3C experiments and ChIP and analyzed data. E.D. analyzed CAGE, ChIP and RNA-seq data. Y.S. designed 3C experiments and performed RNA FISH experiments. K.B. and D.G. designed and produced the AAV vectors. E.Y.C. and K.C.W. helped design and perform the UMLILO knock-in experiment. S.S. carried out mass spectrometry experiments and analyzed data. M.I. analyzed Hi-C data. G.L. and W.-K.S. analyzed ChIP and ChIA-PET data. S.F., Y.S., M.I., E.T.F. and M.M.M. discussed and edited the paper. S.F. and M.M.M. co-wrote the paper. M.M.M. designed experiments, analyzed data and supervised the study.

Corresponding author

Correspondence to Musa M. Mhlanga.

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Competing interests

CSIR (Pretoria) has filed a provisional patent application on behalf of S.F., Y.S., E.D. and M.M.M. claiming some of the concepts described in this publication and licensed the patent to Immunolincs Genomics (Seattle, WA).

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–18

Reporting Summary

Supplementary Table 1

Coordinates and tissue-specific expression of the IPLs

Supplementary Table 2

Chromatin interactions between TNF-responsive genes and lncRNAs in unstimulated HUVECs

Supplementary Table 3

Chromatin interactions between TNF-responsive genes and lncRNAs in HUVECs stimulated with TNF for 30 min

Supplementary Table 4

List of siRNA, LNA and oligonucleotide sequences

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Fanucchi, S., Fok, E.T., Dalla, E. et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat Genet 51, 138–150 (2019).

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