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Nat Genet. 2020 Apr;52(4):378-387. doi: 10.1038/s41588-020-0595-4. Epub 2020 Mar 23.

DNA methylation disruption reshapes the hematopoietic differentiation landscape.

Author information

1
New York Genome Center, New York, NY, USA.
2
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
5
New York University Langone Health, New York, NY, USA.
6
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
New York Genome Center, New York, NY, USA. dlandau@nygenome.org.
10
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. dlandau@nygenome.org.
11
Institute of Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. dlandau@nygenome.org.

Abstract

Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies1-3 and clonal hematopoiesis4,5. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.

PMID:
32203468
DOI:
10.1038/s41588-020-0595-4

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