RESUMO
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 â¼400 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.
RESUMO
Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.
Assuntos
Cromossomos Humanos Par 21 , Síndrome de Down , Síndrome de Down/genética , Síndrome de Down/imunologia , Humanos , Cromossomos Humanos Par 21/genética , Feminino , Transcriptoma , Masculino , Criança , Pré-Escolar , Adulto , Perfilação da Expressão Gênica , Proteoma/metabolismo , AdolescenteRESUMO
Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.