Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation.
Anna S NamNeville DusajFranco IzzoRekha MuraliRobert M MyersTarek H MouhieddineJesus SoteloSalima BenbarcheMichael WaartsFederico GaitiSabrin TahriRoss L LevineOmar Abdel-WahabLucy A GodleyRonan ChalignéIrene M GhobrialDan A LandauPublished in: Nature genetics (2022)
Somatic mutations in cancer genes have been detected in clonal expansions across healthy human tissue, including in clonal hematopoiesis. However, because mutated and wild-type cells are admixed, we have limited ability to link genotypes with phenotypes. To overcome this limitation, we leveraged multi-modality single-cell sequencing, capturing genotype, transcriptomes and methylomes in progenitors from individuals with DNMT3A R882 mutated clonal hematopoiesis. DNMT3A mutations result in myeloid over lymphoid bias, and an expansion of immature myeloid progenitors primed toward megakaryocytic-erythroid fate, with dysregulated expression of lineage and leukemia stem cell markers. Mutated DNMT3A leads to preferential hypomethylation of polycomb repressive complex 2 targets and a specific CpG flanking motif. Notably, the hypomethylation motif is enriched in binding motifs of key hematopoietic transcription factors, serving as a potential mechanistic link between DNMT3A mutations and aberrant transcriptional phenotypes. Thus, single-cell multi-omics paves the road to defining the downstream consequences of mutations that drive clonal mosaicism.
Keyphrases
- single cell
- dna methylation
- rna seq
- wild type
- high throughput
- bone marrow
- stem cells
- endothelial cells
- transcription factor
- acute myeloid leukemia
- genome wide
- gene expression
- poor prognosis
- dendritic cells
- immune response
- induced pluripotent stem cells
- dna binding
- pluripotent stem cells
- squamous cell carcinoma
- heat shock
- squamous cell
- climate change
- cell fate
- signaling pathway
- heat stress
- bioinformatics analysis
- affordable care act
- health insurance