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

• DOI: 10.1016/j.celrep.2024.114599
• Publication Date: 2024-08-08T19:51:33Z
• Authors: Micah G. Donovan; Angela L. Rachubi...; Keith P. Smith; Paula Araya; Katherine A. Waugh; Belinda Enriquez-...; 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
• Keywords: Hypoxia; Cellular stress response; Trisomy

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia dysregulated hematopoiesis have been documented in DS, but underlying mechanisms clinical consequences remain ill defined. We report an integrative multi-omic analysis ∼400 research participants showing that people with DS display transcriptomic signatures indicative elevated heme metabolism hypoxic signaling across lifespan, along chronic overproduction erythropoietin, biomarkers tissue-specific hypoxia, hallmarks stress erythropoiesis. Elevated metabolism, transcriptional erythropoiesis are conserved a mouse model associated overexpression select triplicated genes. These alterations independent hyperactive interferon characteristic DS. results reveal lifelong dysregulation key oxygen-related processes could contribute to developmental