Impact of HSC-derived immune training on granulocyte/macrophage progenitor chromatin landscape

Trained immunity occurs when inflammatory stimulation reprograms myeloid cells to have increased effector functions upon secondary stimulation. Interestingly, the secondary stimulation can occur well beyond the lifetime of an individual myeloid cell, thus memory of immune training must reside in the hematopoietic system. After showing that long-term hematopoietic stem cells (HSCLT) from mice treated with pristane for eight weeks generate trained macrophages, we sought to uncover mechanisms underlying the heritable trained immunity program in myeloid cells. To do this we transplanted HSCLT from pristane mice into congenic recipients, and after 18 weeks of engraftment sorted out donor derived granulocyte monocyte progenitors (GMP). We then analyzed the chromatin landscape and transcriptome using low input chromatin accessibility and transcriptomics sequencing (LiCAT-seq) which allows for the co-generation of RNA-seq and ATAC-seq libraries from the same cellular pool. With this approach we found a unique epigenetic phenotype of reduced chromatin accessibility at metabolic genes in GMP from pristane HSCLT, which resulted in reduced transcription of metabolic genes, leading to reduced metabolism in mature macrophages.