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

Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE

Original Publication: [Cambridge, MA] : Cell Press, c 2012-

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

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.
Competing Interests: Declaration of interests J.M.E. has provided consulting services to Eli Lilly and Co., Gilead Sciences Inc., Biohaven Pharmaceuticals, and Perha Pharmaceuticals.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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R01 AI150305 United States AI NIAID NIH HHS; R01 AI145988 United States AI NIAID NIH HHS; R24 OD035579 United States OD NIH HHS; P30 CA046934 United States CA NCI NIH HHS; UM1 TR004399 United States TR NCATS NIH HHS

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

42VZT0U6YR (Heme)
11096-26-7 (Erythropoietin)

Date Created: 20240809 Date Completed: 20240830 Latest Revision: 20241018

20241018

PMC11479675

10.1016/j.celrep.2024.114599

39120971