Single-cell multi-omics map of human fetal blood in Down syndrome

Andrew R. Marderstein, Marco Zuani, Rebecca Moeller, Jon Bezney, Evin M. Padhi, Shuo Wong, Tim H. H. Coorens, Yilin Xie, Haoliang Xue, Stephen B. Montgomery and Ana Cvejic ()
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Andrew R. Marderstein: Stanford University
Marco Zuani: University of Cambridge
Rebecca Moeller: University of Copenhagen
Jon Bezney: Stanford University
Evin M. Padhi: Stanford University
Shuo Wong: University of Cambridge
Tim H. H. Coorens: Broad Institute of MIT and Harvard
Yilin Xie: Stanford University
Haoliang Xue: University of Cambridge
Stephen B. Montgomery: Stanford University
Ana Cvejic: University of Cambridge

Nature, 2024, vol. 634, issue 8032, 104-112

Abstract: Abstract Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood1–3. Here, to understand dysregulated haematopoiesis in Down syndrome, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human fetal liver and bone marrow samples from 3 fetuses with disomy and 15 fetuses with trisomy. We found that differences in gene expression in Down syndrome were dependent on both cell type and environment. Furthermore, we found multiple lines of evidence that haematopoietic stem cells (HSCs) in Down syndrome are ‘primed’ to differentiate. We subsequently established a Down syndrome-specific map linking non-coding elements to genes in disomic and trisomic HSCs using 10X multiome data. By integrating this map with genetic variants associated with blood cell counts, we discovered that trisomy restructured regulatory interactions to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Furthermore, as mutations in Down syndrome display a signature of oxidative stress4,5, we validated both increased mitochondrial mass and oxidative stress in Down syndrome, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Together, our single-cell, multi-omic resource provides a high-resolution molecular map of fetal haematopoiesis in Down syndrome and indicates significant regulatory restructuring giving rise to co-occurring haematological conditions.

Date: 2024
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DOI: 10.1038/s41586-024-07946-4

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