Hematopoietic stem cells in fetuses with Down syndrome show characteristics that suggest they are primed for differentiation, reflecting changes in blood cell development before birth, according to a recent study.
Down syndrome is characterized by hematological abnormalities, including increased erythrocyte counts and a risk of leukemia, with pathophysiological changes commencing before birth. A recent study investigated the dysregulation of hematopoiesis in Down syndrome through the integration of single-cell transcriptomics, chromatin accessibility, and spatial transcriptomics data.
The analysis encompassed samples from the fetal liver and bone marrow of 15 fetuses with trisomy 21 (Ts21) and 5 fetuses with disomy. The study examined 1,107,552 cells sourced from 18 fetuses, which included 780,299 cells from the liver of those with Ts21, 162,775 cells from the femur of those with Ts21, 110,671 cells from the liver of disomic fetuses, and 53,807 cells from the femur of disomic fetuses.
The differential expression analysis indicated that 62.3% (or 76 out of 122) of the significant peak-gene links related to disomic hematopoietic stem cells (HSCs) showed a notable interaction term, suggesting that peak accessibility was less strongly associated with gene expression in those with Ts21. Out of 1,495 peak-gene links specific to Ts21, just 3.9% (or 59 links) indicated that trisomy enhances the relationship between peak accessibility and gene expression, which was also associated with notable increases in accessibility and gene upregulation in Ts21.
The peaks and genes associated with Ts21 showed a 1.9-fold increase in accessibility (P = 5.6 × 10−12) and a 1.7-fold increase in expression (P = 9.7 × 10−7) when compared to those linked to disomy. The study found that gene expression differences were affected by cell type and environmental context. HSCs in Ts21 fetuses exhibited characteristics that support differentiation.
The researchers created a map specific to Down syndrome that connects non-coding regulatory elements to genes in disomic and trisomic HSCs using 10X multiome data. Findings indicated that trisomy altered regulatory interactions, leading to dysregulation of gene expression critical for erythroid lineage differentiation. Additionally, the study validated mutations associated with oxidative stress, reporting increased mitochondrial mass and oxidative stress levels in Ts21 HSCs.
These results, published in Nature, indicated that trisomy alters the regulatory landscape in fetal hematopoiesis, which may be associated with an increased risk of leukemia in patients with Down syndrome.
Full disclosures can be found in the published study.