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.
Authors
- Paula Araya (ORCID: https://orcid.org/0000-0002-0340-5359)
- Matthew D. Galbraith (ORCID: https://orcid.org/0000-0003-0485-3927)
- Kelly D. Sullivan
- Micah G. Donovan (ORCID: https://orcid.org/0000-0002-3463-2570)
- Kohl T. Kinning (ORCID: https://orcid.org/0000-0002-4861-930X)
- Kyndal A. Schade
- Neetha Paul Eduthan (ORCID: https://orcid.org/0009-0002-6351-0051)
- Joaquı́n M. Espinosa (ORCID: https://orcid.org/0000-0001-9048-1941)
- Katherine A. Waugh (ORCID: https://orcid.org/0000-0002-5288-4990)
- Hannah R. Lyford (ORCID: https://orcid.org/0000-0002-5165-9927)
- Eleanor Britton
- Ross E. Granrath (ORCID: https://orcid.org/0000-0002-9899-831X)
- Keith P. Smith (ORCID: https://orcid.org/0000-0003-2672-6339)
- Angela L. Rachubinski (ORCID: https://orcid.org/0000-0003-1150-3976)
- Belinda A Enriquez-Estrada
Institutions
- University of Kansas Medical Center (US)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114599
- Citations
- 8
- Primary Topic
- Down syndrome and intellectual disability research
- Type
- article
- Field-Weighted Citation Impact
- 4.34
Funders
- Boettcher Foundation
- Gilead Sciences
- Global Down Syndrome Foundation
- Institute of Translational Health Sciences
- Deciphera Pharmaceuticals
- Anna and John J. Sie Foundation
- National Institutes of Health
- NIH Office of the Director
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences
- University of Colorado School of Medicine, Anschutz Medical Campus
- Division of Cardiothoracic Surgery, University of Colorado School of Medicine, Anschutz Medical Campus
- Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Anschutz Medical Campus