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Nat Genet. 2019 Jan;51(1):138-150. doi: 10.1038/s41588-018-0298-2. Epub 2018 Dec 10.

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

Author information

1
Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
2
BTRI, CSIR Biosciences, Pretoria, South Africa.
3
Department of Medicine, Università degli Studi di Udine, Udine, Italy.
4
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
5
Department of Infectious Diseases/Virology, BioQuant Center, Heidelberg University Hospital, Heidelberg, Germany.
6
Heidelberg Partner Site, German Center for Infection Research (DZIF), Heidelberg, Germany.
7
Department of Dermatology, Stanford University, Stanford, CA, USA.
8
Biomedical Technologies Group, CSIR Biosciences, Pretoria, South Africa.
9
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Boston, MA, USA.
10
Cluster of Excellence CellNetworks, Heidelberg, Germany.
11
College of Informatics, Huazhong Agricultural University, Wuhan, China.
12
School of Computing, National University of Singapore, Singapore, Singapore.
13
Genome Institute of Singapore, Singapore, Singapore.
14
Gene Expression and Biophysics Group, Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. arhat@mhlangalab.org.
15
Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal. arhat@mhlangalab.org.

Abstract

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.

PMID:
30531872
DOI:
10.1038/s41588-018-0298-2
[Indexed for MEDLINE]

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