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

doi:10.1016/j.celrep.2024.114599

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

Cell Rep. 2024 Aug 27;43(8):114599. doi: 10.1016/j.celrep.2024.114599. Epub 2024 Aug 8.

Authors

Affiliations

¹ 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.
² 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.
³ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴ 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.
⁵ 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.
⁶ 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. Electronic address: [email protected].
⁷ 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. Electronic address: [email protected].

Abstract

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.

Keywords: CP: Developmental biology; CP: Metabolism; erythropoietin; heme; hypoxemia; hypoxia; macrocytosis; red blood cells; stress erythropoiesis.

MeSH terms

Adolescent
Adult
Animals
Child
Child, Preschool
Down Syndrome* / genetics
Down Syndrome* / metabolism
Down Syndrome* / pathology
Erythropoiesis*
Erythropoietin / metabolism
Female
Heme* / metabolism
Humans
Hypoxia* / metabolism
Male
Mice
Signal Transduction*
Stress, Physiological
Transcriptome / genetics

Substances

Heme
Erythropoietin

Abstract

MeSH terms

Substances

Grants and funding