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Title: Immune genes are primed for robust transcription by proximal lncRNAs located in nuclear compartments
Accumulation of H3K4me3 epigenetic marks on immune-related gene promoters underlies robust transcription during trained immunity. However, the molecular basis for this remains unknown. Here we show 3D chromatin topology enables immune genes to engage in chromosomal contacts with a new subset of lncRNAs we have defined as immune-gene priming lncRNAs (IPLs).
We show that the prototypical IPL, UMLILO, acts in cis to direct the WDR5/MLL1 complex across the chemokine promoters facilitating their H3K4me3 epigenetic priming. This mechanism is shared amongst several trained immune genes. β-glucan-mediated training epigenetically reprograms immune genes by upregulating IPLs in an NFAT-dependent manner. The murine chemokine TAD lacks an IPL and the Cxcl genes are not trained. Strikingly, the insertion of UMLILO into the chemokine TAD in murine macrophages resulted in training of Cxcl genes. This provides strong evidence that lncRNA-mediated regulation is central to the establishment of trained immunity.