Multimodal analysis of dysregulated heme metabolism, hypoxic signaling, and stress erythropoiesis in Down syndrome
Micah G. Donovan,
Angela L. Rachubinski,
Keith P. Smith,
Paula Araya,
Katherine A. Waugh,
Belinda Enriquez-Estrada,
Eleanor C. Britton,
Hannah R. Lyford,
Ross E. Granrath,
Kyndal A. Schade,
Kohl T. Kinning,
Neetha Paul Eduthan,
Kelly D. Sullivan,
Matthew D. Galbraith,
Joaquin M. Espinosa
Affiliations
Micah G. Donovan
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Angela L. Rachubinski
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Section of Developmental Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Keith P. Smith
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Paula Araya
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Katherine A. Waugh
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
Belinda Enriquez-Estrada
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Eleanor C. Britton
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Hannah R. Lyford
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Ross E. Granrath
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Kyndal A. Schade
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Kohl T. Kinning
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Neetha Paul Eduthan
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Kelly D. Sullivan
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Matthew D. Galbraith
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Corresponding author
Joaquin M. Espinosa
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Corresponding author
Summary: 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.
