Multimodal analysis of dysregulated heme metabolism, hypoxic signaling, and stress erythropoiesis in Down syndrome

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of ∼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS. [Display omitted] •Multi-omic analysis indicates elevated hypoxic signaling and heme metabolism in Down syndrome•These signatures track with hallmarks of stress erythropoiesis and immune remodeling•The Dp16 mouse model of Down syndrome recapitulates these molecular phenotypes•These events occur independently of hyperactive interferon and JAK/STAT signaling Donovan et al. report that individuals with Down syndrome display multi-omic signatures indicative of hypoxic signaling and altered heme metabolism, along with signs of stress erythropoiesis. These signatures associate with key proteomic and immune cell changes in Down syndrome and are independent of hyperactive interferon signaling.