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

Cell Reports (Aug 2024)

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

Journal volume & issue: Vol. 43, no. 8
p. 114599

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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