Epigenetic profiling across hematopoietic stages identifies genomic loci with conserved chromatin alterations after infection
Infection leads to durable cell-autonomous changes in hematopoietic stem and progenitor cells (HSPCs), resulting in production of innate immune cells with heightened immune function. The mechanisms underlying this phenomenon, termed central trained immunity, remain poorly understood. We hypothesized that infection induces histone modifications in chromatin, leading to changes in chromatin accessibility that are passed down from HSPCs to myeloid progenitors, monocytes and macrophages. To test this hypothesis, we conducted genome-wide surveillance of activating histone marks H3K27Ac and H3K4me3 and transposon accessibility of chromatin in hematopoietic stem cells, multipotent progenitor 3, granulocyte-monocyte progenitors, monocytes and macrophages of naïve versus Mycobacterium avium infected mice. While activating histone marks and chromatin accessibility were increased broadly in biological responses to interferon and cytokine signaling. Consistent with this finding, transcription factor binding motifs related to interferon signaling, including IRFs, NF-kB, and CEBP, were highly enriched across cell types. However, activating histone marks and increased chromatin accessibility were commonly induced at only a few loci including Irf1 and Gbp6 across multiple stages of differentiation. In summary, processing of inflammatory signaling upon systemic infection leads to epigenetic changes in HSPCs, and these changes are conserved at a small number of genetic loci in downstream monocytes. Overall design: To understand how the overall chromatin accessibility landscape is changed in myeloid cells and their progenitors upon M. avium infection, we performed single cell assay for transposase accessibility sequencing (scATAC-seq) on targeted HSPCs and downstream terminally differentiated cells, including Mo/Macs, neutrophils, and B cells, from pooled murine samples from M. avium infected and naïve mice.