Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments
Stephanie Fanucchi, Ezio T. Fok, Emiliano Dalla, Youtaro Shibayama, Kathleen Börner, Erin Y. Chang, Stoyan Stoychev, Maxim Imakaev, Dirk Grimm, Kevin C. Wang, Guoliang Li, Wing-Kin Sung & Musa M. Mhlanga
Published in: Nature Genetics 51, 2019, 138–150
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-dimen-sional 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 chemo-kine 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 establish-ment of trained immunity.