Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • September 22, 2022

Research

keywords

  • Clonal Hematopoiesis
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A

Identity

PubMed Central ID

  • PMC10068894

Scopus Document Identifier

  • 85138534248

Digital Object Identifier (DOI)

  • 10.1038/s41588-022-01179-9

PubMed ID

  • 36138229

Additional Document Info

volume

  • 54

issue

  • 10