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DNA methylation disruption reshapes the hematopoietic differentiation landscape
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Journal Article
DNA methylation disruption reshapes the hematopoietic differentiation landscape
2020
Overview
Mutations in genes involved in DNA methylation (DNAme; for example,
TET2
and
DNMT3A
) are frequently observed in hematological malignancies
1
–
3
and clonal hematopoiesis
4
,
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.
Single-cell analysis of mouse hematopoietic stem cells shows that mutations in DNA methylation genes change the frequencies of erythroid versus myelomonocytic progenitors, owing to differential CpG enrichment in transcription factor binding motifs.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 13/31
/ 38/39
/ 45/100
/ 45/23
/ 45/77
/ 45/91
/ 64/60
/ Analysis
/ Animal Genetics and Genomics
/ Animals
/ Binding
/ Biomedical and Life Sciences
/ Cell Differentiation - genetics
/ DNA
/ DNA (Cytosine-5-)-Methyltransferases - genetics
/ DNA-Binding Proteins - genetics
/ Genomes
/ Hematopoietic Stem Cells - physiology
/ Humans
/ Letter
/ Male
/ Mice
/ Mutation
/ Priming
