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

   

Authors:	Nam, A. S.; Dusaj, N.; Izzo, F.; Murali, R.; Myers, R. M.; Mouhieddine, T. H.; Sotelo, J.; Benbarche, S.; Waarts, M.; Gaiti, F.; Tahri, S.; Levine, R.; Abdel-Wahab, O.; Godley, L. A.; Chaligne, R.; Ghobrial, I.; Landau, D. A.
Article Title:	Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation
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. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords:	adult; controlled study; human tissue; middle aged; human cell; somatic mutation; genetics; mutation; nonhuman; mouse; cd34 antigen; multiple myeloma; gene expression; bone marrow; cell maturation; animal experiment; cohort analysis; transcription factor; cell differentiation; dna methylation; blood sampling; bone marrow biopsy; cpg island; cancer stem cell; hematopoiesis; dna flanking region; upregulation; cell marker; dna methyltransferase; dna modification methylases; granulocyte colony stimulating factor; transcriptome; myeloid progenitor cell; dna (cytosine 5) methyltransferase; leukemia remission; cyclic amp responsive element binding protein; stat protein; stem cell expansion; dna methyltransferase 3a; tumor microenvironment; genotyping; methylome; interferon regulatory factor 7; clonal hematopoiesis; transcription factor gata 2; polycomb repressive complex 2; humans; human; male; female; article; megakaryocyte erythroid progenitor; differential expression analysis; gene set enrichment analysis; single cell rna seq; multiomics; dna (cytosine-5-)-methyltransferases
Journal Title:	Nature Genetics
Volume:	54
Issue:	10
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2022-10-01
Start Page:	1514
End Page:	1526
Language:	English
DOI:	10.1038/s41588-022-01179-9
PUBMED:	36138229
PROVIDER:	scopus
PMCID:	PMC10068894
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85138534248&doi=10.1038%2fs41588-022-01179-9&partnerID=40&md5=cbee0a7a458da86c633410221aec177f
Notes:	Article -- Export Date: 1 November 2022 -- Source: Scopus

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