Graduate Student University of North Carolina at Chapel Hill Chapel Hill, North Carolina
Innate Immune memory or trained immunity is characterized by the acquisition of epigenetic marks at the promoters of innate immune genes. These epigenetic marks can be acquired through various stimuli including the use of agents such as beta glucan and vaccination by Bacillus Camille Guerin (BCG). However, the mechanism around how this "memory" is mechanistically "written" has remained elusive until recently. In this presentation the upstream molecular events that coordinate trained immunity and transcriptionally poised state of inflammatory genes are described. Here we describe a new class of lncRNAs, immune gene proximal lncRNAs (IP-lncRNA), which exploit 3D nuclear topology permitting them to be brought in close proximity to poised pro- inflammatory genes. We functionally characterize UMLILO a prototypic IP-lncRNA that is brought in close proximity to the proinflammatory chemokine promoters by pre- formed chromosomal contacts. Depletion of UMLILO is sufficient to abrogate chemokine transcription. Mice lack an UMLILO homolog and correspondingly lack H3K4me3 priming at the chemokine locus. Acting in cis, UMLILO uses the pre-formed Topologically Associating Domain to direct the WDR5-MLL1 complex across the chemokine promoters, facilitating the deposition H3K4me3 and the acquisition of trained immunity. This creates a new paradigm for how nuclear architecture and lncRNA regulation orchestrate the acquistion of innate immune memory facilitating the rapid transcription of poised highly responsive inflammatory genes. Since vaccination by BCG also triggers trained immunity we investigated whether vaccination led to upregulation of IP-lncRNAs at single cell level and the subsequent enhanced killing by innate immune cells. We show that BCG vaccination leads to increased expression of UMLILO and other lncRNAs placing these noncoding genomic elements as important biomarkers of the activity of the immune system and inflammation.
What is Innate Immune Memory or Trained immunity
How is this memory encoded by 3D chromatin architecture & lncRNAs
How do species differences in noncoding elements influence trained immunity.
How does vaccination influence trained immunity and epigenetic changes in myeloid cells?
Using noncoding elements as biomarkers at single cell resolution