Genomic Analysis Of Bone Marrow Progenitors During Viral Infection Reveals Novel Dendritic Cell Regulators

Abstract

Abstract Dendritic cells (DC) play a central role in immune responses and can broadly subdivided into conventional (c) and plasmacytoid (p) DCs. We and others have described several adaptations of DCs and their progenitors during acute and chronic infections, including impaired DC development, maturation and altered cytokine production. To understand the underlying mechanisms we determined the transcriptional and chromatin landscapes of bone marrow (BM) DC progenitors from lymphocytic choriomeningitis virus (LCMV) infected mice, via RNA-Seq and ATAC-Seq, respectively. Initial analysis indicated that infection induced multiple alterations in gene signatures, including type-I-interferon signaling and metabolic pathways, as well as changes in chromatin accessibility, which were more enriched within intergenic regions. We next used the Taiji algorithm, which integrates chromatin accessibility and gene expression to assess the global importance of transcription factors (TFs) at the systems level. This analysis identified 11 known DC regulators and 24 TFs with no previous connection to DC biology. Knock-down experiments revealed that Glucocorticoid Modulatory Element Binding Protein 1 (Gmeb1), which was predicted to exhibit increased activity in progenitors from LCMV-infected mice, suppressed DC development and maturation. On the other hand, Zinc Finger Protein 524 (Zfp524), whose activity was predicted to be reduced in progenitors from LCMV-infected mice, promoted pDC cytokine production while inhibiting the same function in cDCs. These results highlight two novel TFs that regulate DC development and/or function, deepening our understanding of DC biology and providing potential new targets for DC-based immunotherapies.