期刊
NATURE GENETICS
卷 54, 期 10, 页码 1514-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01179-9
关键词
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资金
- Burroughs Wellcome Fund Career Award for Medical Scientists
- National Institutes of Health Director's Early Independence Award [DP5 OD029619]
- Starr Cancer Consortium
- National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health [F30HL156496]
- Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health [T32GM007739]
- American Society of Hematology Fellow-to-Faculty Scholar Award
- Lymphoma Research Foundation
- Marie Sklodowska-Curie fellowships
- Dr Miriam and Sheldon G. Adelson Medical Research Foundation
- Stand Up To Cancer Dream Team Research Grant [SU2C-AACR-DT-28-18]
- Burroughs Wellcome Fund Career Award for Medical Scientists, Valle Scholar Award
- National Institutes of Health Director's New Innovator Award [DP2-CA239065]
- Chan Zuckerberg Initiative Award
- Leukemia Lymphoma Society Career Development Program Award
- Mark Foundation Emerging Leader Award
- NHLBI [R01HL145283]
- National Human Genome Research Institute, Center of Excellence in Genomic Science [RM1HG011014]
Somatic mutations in cancer genes, specifically DNMT3A R882 mutation, can lead to clonal hematopoiesis and alter the differentiation of myeloid progenitor cells. Using multi-modality single-cell sequencing, researchers have identified dysregulated expression of lineage and leukemia stem cell markers, as well as specific DNA methylation patterns associated with DNMT3A mutations. This study sheds light on the downstream consequences of these mutations and provides a potential mechanistic link between genotype and phenotype.
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. Multi-modality single-cell sequencing determines genotype, transcriptome and methylome information in cells from individuals with DNMT3A R882 mutated clonal hematopoiesis, allowing for the comparison of mutant and wild-type cells from the same individuals.
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