We performed high throughput transcriptomic profiling with RNA sequencing (RNA-Seq) to uncover network responses in human THP-1 monocytes treated with high glucose (HG). Our data analyses revealed that interferon (IFN) signaling, pattern recognition receptors, and activated interferon regulatory factors (IRFs) were enriched among the HG-upregulated genes. Motif analysis identified an HG-responsive IRF-mediated network in which interferon-stimulated genes (ISGs) were enriched. Notably, this network showed strong overlap with a recently discovered IRF7-driven network relevant to Type 1 diabetes. We next examined if the HG-regulated genes possessed any characteristic chromatin features in the basal state by profiling 15 active and repressive chromatin marks under normal glucose conditions using chromatin immunoprecipitation linked to promoter microarrays. Composite profiles revealed higher histone H3 lysine-9-acetylation levels around the promoters of HG-upregulated genes compared with all RefSeq promoters. Interestingly, within the HG-upregulated genes, active chromatin marks were enriched not only at high CpG content promoters, but surprisingly also at low CpG content promoters. Similar results were obtained with peripheral blood monocytes exposed to HG. These new results reveal a novel mechanism by which HG can exercise IFN-α-like effects in monocytes by upregulating a set of ISGs poised for activation with multiple chromatin marks.