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.
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.
Cell Rep. 2024 Aug 27;43(8):114599. doi: 10.1016/j.celrep.2024.114599. Epub 2024 Aug 8.
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.
唐氏综合征（Down syndrome，DS）是由 21 号染色体三体（trisomy 21，T21）引起的一种遗传性疾病，其特征为神经发育迟缓、衰老加速以及多种伴发疾病风险增加。目前已有研究记录了唐氏综合征患者存在低氧血症和造血功能失调，但潜在的发病机制和临床后果仍未明确。我们报告了一项对约 400 名研究参与者的综合多组学分析，结果表明，唐氏综合征患者在整个生命周期中表现出转录组特征，表明血红素代谢升高和缺氧信号转导增强，同时伴有促红细胞生成素过度产生、组织特异性缺氧生物标志物升高以及应激性红细胞生成的特征。在唐氏综合征的小鼠模型中，血红素代谢升高、缺氧转录组特征和应激性红细胞生成是保守的，并且与选定的三倍基因表达过度有关。这些改变与唐氏综合征特征性的过度活跃的干扰素信号无关。这些结果揭示了与关键氧气相关过程的终生失调，这可能导致唐氏综合征的发育和临床特征。
